No retraction, correction or concern found when last checked on Oct 26, 2026.

Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments

Kazuhiro Maeda, Ken Yoshida, Tetsuro Nishizawa and 7 more

International Journal of Molecular Sciences · 2022 · Review · CC BY

Abstract

Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients’ quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1RA is a systemic autoimmune disease, occurring more commonly in women. It is prevalent in approximately 0.5–1% of the population. The disease is characterized by persistent synovitis, which causes the destruction of cartilage and bone, and it eventually leads to the deformation of joints. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities deteriorate the quality of life of patients and can further exacerbate medical complications and cause early death. RA-associated social problems are increased socio-economic burdens, deteriorated labor capacity, and decreased social participation. Therefore, early diagnosis of RA, followed by the initiation of therapeutic intervention, is critical because the exacerbation of osteoarticular destruction is avoidable. To achieve this, osteoarticular destruction may be prevented by active treatment based on the Treat to Target concept, i.e., the efficacy of a medication regimen is strictly assessed every 1–3 months, and the regimen found to be ineffective is quickly switched to a different regimen with a higher therapeutic intensity. The goal of RA treatment is to achieve clinical, structural, and functional remission states. Clinical remission refers to a state where the resolution of inflammatory responses, including swollen and tender joints, is demonstrated using clinical scores, such as disease activity score-28, simple disease activity index, and clinical disease activity index. Structural remission, a state where the progression of articular destruction is almost stopped, is assessed with the modified Total Sharp Score. Functional remission, a state where physical function is no longer reduced, is evaluated using the health assessment questionnaire. Even when pain and swelling are mitigated and clinical remission is achieved due to therapeutic intervention, the progression of articular destruction might still occur, resulting in functional deterioration in some cases. Therefore, it is important to achieve all three remission states.

2Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. When the immune system is impaired, synoviocytes express receptor activator of nuclear factor-κB ligand (RANKL) and produce proteases, which induce bone destruction and cartilage destruction, respectively. The molecular mechanisms of inflammatory cytokines on osteoblast differentiation have been studied, and their effects on bone metabolism are becoming clearer. As a result, various therapeutic agents have been developed to target inflammatory cytokines. Furthermore, novel treatments targeting T cells and mediators of inflammatory cytokines have been developed, which are now used clinically. The elucidation of mechanisms causing inflammation and bone destruction enables a more targeted approach in RA that are resistant to conventional treatment options. In this paper, we mainly review bone metabolism under physiological and RA conditions and finally describe the effects of therapeutic intervention against RA on the bone. In particular, their effects on bone metabolism contributing to bone mineral density changes and fracture risks are described in detail. RA-associated cartilage destruction has been described in previous articles.

2.1. Bone Remodeling

3Bones serve as supporting tissues and calcium reservoirs. They have long been recognized as hormone targets involved in calcium metabolism. However, with recent advances in molecular biology, it has been clarified that bones also produce hormones and serve as endocrine organs that contribute to the maintenance of homeostasis in living organisms. Bone turnover occurs and bone mass is maintained through repeated resorption of mature bones and formation of new bones at the site of resorption. This bone remodeling cycle is a constant process, and approximately 10% of bone mass is replaced yearly in humans. Bone remodeling is controlled by osteoblasts, osteoclasts, and osteocytes (Figure 1).

2.2. Osteoblasts and Osteocytes

4Osteoblasts produce bone matrix proteins, such as type I collagen, osteocalcin, bone sialoprotein, and osteopontin, in a differentiation stage-dependent manner. Osteoblasts have a total lifespan of 2–3 months. They eventually become apoptotic, remain on the bone surface as quiescent bone lining cells, embed within self-secreted bone matrix proteins, or differentiate into osteocytes. In recent years, it has been reported that microRNAs are involved in the differentiation of mature osteoblasts into osteocytes.

5Osteoblasts are derived from undifferentiated mesenchymal cells and are believed to differentiate from the same progenitor cells as chondrocytes, adipocytes, myocytes, and fibroblasts. Differentiation from progenitor cells to tissue-specific cells is regulated by tissue-specific transcription factors (Figure 1).

6Runt-related transcription factor (Runx) 2 from the Runx family of transcription factors has been identified as a master transcription factor essential for osteoblast differentiation. It is homologous to one of the segmentation genes in Drosophila. Runx1 is recognized as the gene responsible for the development of acute myeloid leukemia, and Runx1 knockout mice are embryonically lethal due to the complete absence of hematopoiesis in the fetus. To identify the function of the Runx family transcription factors in hematopoiesis, Runx2 knockout mice were generated. These mice were born without bones, indicating that Runx2 has an important role in osteoblast differentiation. Runx2 induces the expression of osteocalcin, bone sialoprotein, and osteopontin and regulates the expression of Osterix, a downstream transcription factor. Bone morphogenetic proteins and wingless-related MMTV integration site (Wnt)s are also known cytokines that promote osteogenesis.

7Wnt proteins suppress apoptosis in osteoblast precursor cells prior to determination of cell differentiation, thus facilitating osteoblast differentiation. In particular, Wnt1 produced by mesenchymal cells promotes bone formation. Studies in knockout and transgenic mice have found that Wnt10b facilitates osteogenesis and increases bone mass. In vitro studies have revealed that Wnt6, Wnt10a, and Wnt10b suppress the differentiation of mesenchymal stem cells to adipocytes and facilitate the differentiation of mesenchymal stem cells to osteoblasts through the canonical Wnt pathway. Additionally, secreted Frizzled-related proteins (sFRP)1 and sFRP4, which are both Wnt inhibitory factors, suppress the differentiation of mesenchymal stem cells to osteoblasts (Figure 1). These results indicate that the canonical Wnt pathway is essential for mesenchymal stem cell differentiation to osteoblast-lineage cells.

8Although osteocytes constitute 95% of the bone tissue, their roles remain unclear to date. Recent molecular biological advances have facilitated the identification of osteocytes as a source of RANKL, an osteoclast differentiation factor (Figure 1). With the finding that bone mass markedly increases in mice with osteocyte-specific RANKL gene deficiency, RANKL produced by osteocytes is shown to be an important regulator of bone remodeling. Meanwhile, stimulation with parathyroid hormone, mechanical loading, and stimulation by interleukin-6 (IL-6) cytokine family suppress the expression of SOST that encodes sclerostin responsible for the suppression of the canonical Wnt signaling pathway. It has been demonstrated that osteocytes play a commander role in bone remodeling that balances bone resorption and formation. In the future, understanding the role of osteocytes in bone remodeling at the molecular biological level will help establish additional treatment methods for skeletal disorders.

2.3. Osteoclasts and Bone Resorption

9Osteoclasts are multinucleated giant cells, which are the only cells that manage bone resorption in vivo. The progenitor cells of osteoclasts are monocytes and macrophage-lineage cells. The differentiation of osteoclast progenitors into osteoclasts is tightly regulated by osteoblasts and osteocytes, which express RANKL and macrophage colony-stimulating factor (M-CSF) cytokines required for stimulating the differentiation of progenitor cells into osteoclasts. While the expression of M-CSF by osteoblasts is constitutive, that of RANKL is induced by bone resorbing factors, such as 1α,25-dihydroxy-vitamin D3 [1α,25(OH)2D3], parathyroid hormone, and pro-inflammatory cytokines. Osteoclast progenitors express c-Fms and receptor activator NF-κB (RANK), the respective receptors of M-CSF and RANKL, facilitating their stimulation from both ligands for their differentiation into osteoclasts. In addition, osteoblasts and osteocytes secrete osteoprotegerin (OPG), a decoy receptor of RANKL, which inhibits RANKL–RANK interaction to suppress bone resorption (Figure 1).

10RANK signal transduction requires an adapter molecule, tumor necrosis factor (TNF) receptor-associated factor 6, which activates mitogen-activated protein kinase, nuclear factor κB, and c-Fos that eventually induce nuclear factor of activated T cell c1 (NFATc1), a master transcription factor involved in osteoclast differentiation and function. NFATc1 promotes the expression of osteoclast-specific genes, such as dendritic cell-specific transmembrane protein, essential for cell fusion, and a proteolytic enzyme cathepsin K. In addition, co-stimulating signals mediated by immunoglobulin-like receptors play a key role in the activation of NFATc1.

2.4. Coupling Factors in Bone Metabolism

11OPG knockout mice exhibit an osteoporotic phenotype owing to excessive bone resorption. However, they also exhibit accelerated bone formation. Administration of risedronate, a bisphosphonate that suppresses osteoclast bone-resorbing activity, results in marked suppression of both bone formation and resorption, suggesting the coupling of bone resorption and formation.

12During bone remodeling, osteoclasts potentially promote bone formation by osteoblasts through the release of bone matrix embedded growth factors, such as insulin-like growth factor I and transforming growth factor-beta (TGF-β), during bone resorption (Figure 1). On the other hand, in mice with osteoclast-specific cathepsin K deficiency, osteoclast function is suppressed, and bone resorption is decreased, while osteoclast and osteoblast differentiations are promoted. This suggests that molecules expressed by osteoclasts are more important for osteoblast differentiation than the growth factors present in the bone matrix. Accordingly, ephrin-B2, collagen triple helix repeat containing 1, sphingosine-1-phosphate (S1P), C3a, Wnt1, Wnt10b, bone morphogenetic protein 6, Cardiotropin-1, and platelet-derived growth factor-BB have been reported as coupling factors that promote osteoblast differentiation (Figure 1). More recently, an inverted RANKL signaling pathway in which osteoclast-derived membrane vesicles containing RANK promote bone formation via RANKL in osteoblasts, and the activation of the PI3K-Akt-mammalian target of rapamycin complex 1 (mTORC1) pathway, have been described during osteoblast differentiation. Establishing the molecular basis underlying bone metabolism coupling will help with the development of new drugs that improve bone metabolism by promoting bone formation, independent of bone resorption.

3.1. Predisposing Factors and Associated Systemic Effects

13The incidence of osteoporosis in patients with RA is known to be high and is approximately twice as high as that in the general population of similar age; the former population has been reported to have a 1.3-fold increased risk of femoral fractures and a 2.4-fold increased risk of spinal fractures. Osteoporosis has also been shown as a complication found in approximately 40% of patients with RA in their 60s. Possible factors contributing to the high incidence of osteoporosis in patients with RA include inflammation, deteriorated cortical bone quality, adverse reactions to drugs used for treating RA, such as glucocorticoids, immobility, and nutritional effects, such as vitamin D deficiency.

14Inflammatory cytokines induced by transcription factor, such as NF-kappa B, cause inflammation, with IL-6 in particular increasing C-reactive protein. Furthermore, TNF-α and IL-6 promote the expression of RANKL in mesenchymal cells, such as synovial fibroblasts. The serum level of dickkopf-1 (DKK1), an inhibitor of the canonical Wnt pathway important for osteogenesis, has been reported to be elevated in RA. DKK1 is known to be induced by TNF-α, and osteogenesis in the whole body is suppressed in RA. Some studies have shown that inflammatory environment directly suppresses osteogenesis. Furthermore, elevated serum DKK1 serves to promote bone resorption because the canonical Wnt pathway is involved in OPG production. Thus, under RA condition, bone resorption is increased, whereas osteogenesis is decreased. Therefore, the coupling between bone formation and resorption tends to be disrupted, and the bone mineral density decreases.

15Studies using high-resolution peripheral quantitative computed tomography have shown that cortical bone porosity is increased in patients with RA. Since the cortical bone porosity has a major effect on mechanical bone strength, patients with RA have a greater risk of fragility fractures than healthy individuals.

16The effects of steroids on the bone strength cannot be overlooked because 20%–40% of patients with RA reportedly undergo treatment with oral glucocorticoids. An excessive amount of glucocorticoids suppresses osteogenesis through initiation of apoptosis of osteoblasts, inhibition of Wnt signaling pathways, and regulation of microRNA expression in osteoblasts and osteocytes. Excessive glucocorticoids also suppress the OPG expression and promote bone resorption.

17Mechanical shear stress, such as fluid flow-induced shear stress, causes the suppression of sclerostin expression via Akt and the promotion of the canonical Wnt pathway via the Hippo pathway, which are mediated by Piezo effect in osteocytes. Thus, moderate gravity loads are important for maintaining bone mass. The bone mass change is decreased in patients with RA because they tend to be immobile due to pain and skeletal deformity.

18Another metabolic factor affecting bone metabolism is vitamin D, which is a fat-soluble vitamin discovered as antirachitic factor. However, 1,25 OH2D3 has been identified as the final active form responsible for physiological effects of vitamin D. 1,25 OH2D3 regulates calcium metabolism through the promotion of calcium absorption from the small intestine and bone metabolism through reduction in secretion of parathyroid hormones. An inverse correlation between serum 25-hydroxyvitamin D3, a precursor of 1,25 OH2D3, and fracture risk has been reported. In addition to its effects on bone and calcium metabolism, vitamin D may be involved in the regulation of immune responses. 25-Hydroxyvitamin D levels have been reported to be significantly associated with RA disease activity and a significant predisposition to osteoporosis.

3.2.1. Differentiation of Osteoclasts under RA Condition

19In physiological bone metabolism, osteoclasts are found inside the bone, in which they resorb the old bone and trigger osteogenesis via coupling factors. However, under arthritic conditions, osteoclasts are found in the synovial membrane inside the articular capsule and destroy the bone externally. It has not been clarified whether osteoclasts destroying the bone externally in RA and metastatic bone tumors are identical to osteoclasts found in physiological bone metabolism.

20Hasegawa et al. have identified arthritis-specific osteoclast precursors using two-photon excitation microscopy and single-cell analysis techniques in the inflamed synovial tissue collected from the knee joints of collagen-induced arthritis (CIA) model mice and have named these precursors as arthritis-associated osteoclastogenic macrophages (AtoMs). AtoMs differentiate into osteoclasts in joints after bone-marrow-derived cells flow into the joints through the bloodstream. The AtoM differentiation is RANKL-dependent, and TNF-α has a synergistic effect. Unlike osteoclasts in physiological bone metabolism, differentiation into osteoclasts is regulated by the transcription factor forkhead box protein (Fox) m1 and is hampered by Foxm1 inhibitors in arthritis. Studies using clinical specimens have also found similar cells, whose differentiation was impeded by the addition of a Foxm1 inhibitor. Narisawa et al. analyzed the characteristics of dendritic cell-derived osteoclasts (DC-OCs) prepared by the addition of macrophage colony-stimulating factor and RANKL to dendritic cells, which were obtained from human peripheral blood monocytes through differentiation induction with granulocyte-M-CSF, IL-4, and lipopolysaccharide. DC-OCs had a larger size and an increased capacity for bone resorption than monocyte-derived osteoclasts (Mo-OCs). Moreover, in contrast to Mo-OCs, DC-OCs retained the abilities of dendritic cells and were positive for costimulatory molecules, such as CD80 and CD86, and for CD11c and fractalkine receptors. Furthermore, T cells co-cultured with DC-OCs were activated. These data indicate that DC-OCs can serve as both osteoclasts and dendritic cells. The detection of DC-OCs in the synovial tissue of patients with RA suggests the involvement in osteoarticular destruction in RA. The detailed understanding of molecular characteristics of these osteoclasts emerging under RA condition is expected to help establish a molecular basis for new therapy against osteoarticular destruction.

3.2.2. Effects of T Cells on Osteoarticular Destruction

21RANKL is essential for the differentiation of AtoMs into pathogenic osteoclasts and the formation of DC-OC, respectively. For years, it has been controversial as to which cells are an important source of RANKL in the RA condition.

22CD4-positive T cells, which are helper T cells, are clearly important in RA pathogenesis based on the following findings: (1) CD4-positive T-cell-depleted mice are protected from arthritis; (2) genome-wide association studies have reported CD4-positive T-cell-related genes as RA susceptibility genes; and (3) abatacept (ABT), which is a T cell co-stimulation modulator by binding to CD80 and CD86 receptors, thereby suppressing T cell activation and B cell stimulation, is effective against RA. Activated CD4-positive T cells differentiate into various helper T cell subsets depending on the surrounding cytokine environment. Previously, RA pathogenesis has been thought to be mediated by Th1 cells. However, Th1 cells produce interferon-γ, by which osteoclast differentiation is strongly hampered. Later studies in knockout mice have shown the importance of Th17 cells for osteoclast differentiation in the presence of inflammation. Th17 cells express IL-17 and promote the production of RANKL and inflammatory cytokines by synoviocytes. Furthermore, IL-17 also induces the expression of inflammatory cytokines in cells of the innate immune system and fibroblasts with other inflammatory cytokines, creating a microenvironment to facilitate local osteoclast differentiation. Differentiation into various helper T cell subsets is plastic depending on the surrounding environment. Foxp3-positive regulatory T cells impede the effector T cell function. In an arthritic environment, some subsets of Foxp3+CD4+ T cells have been reported to cease the Foxp3 expression and transdifferentiate into Th17 cells (called exFoxp3Th17 cells) in response to the IL-6 stimulus from synovial fibroblasts. ExFoxp3Th17 cells are considered to be involved in the aggravation of osteoarticular destruction because they express RANKL at a high level. However, since the osteoclast-inducing ability of ExFoxp3Th17 cells alone is low, synovial fibroblasts are considered an important primary source of RANKL in RA (Figure 2).

23The efficacy of anti-IL-17A antibodies has also been shown in the CIA model. Furthermore, a study using clinical specimens from arthritis patients has reported the retention of IL-17 or Th17 cells in the synovial fluid. However, the real-world data of treatments targeting the IL-23/IL-17 axis against RA have shown relatively modest success compared with other indications, such as psoriatic arthritis. A future research task is how to improve mouse model studies to better simulate the understanding of RA pathology in humans.

3.2.3. Effects of B Cells on Osteoarticular Destruction

24The importance of B cells in RA has been demonstrated by the therapeutic efficacy of the CD20 monoclonal antibody rituximab, a B-cell-neutralizing antibody, in patients with RA. The serum anticitrullinated protein antibody (ACPA) titer correlates positively with the severity of osteoarticular destruction. Immune complexes containing ACPAs have been shown to activate Fcγ receptors on osteoclast precursors and, thereby, promote osteoclast differentiation. Peripheral helper T cells have recently been identified as a new T cell subset. Studies have reported that peripheral helper T cells are increased in the ACPA-positive patients with RA and react with B cells to promote the production of autoantibodies (Figure 2). Substances targeting these cells are expected to enable the regulation of ACPA, which is a poor prognostic factor of articular destruction.

25Meanwhile, in vitro studies using clinical specimens have shown that RANKL is expressed in B cells found in the RA synovial fluid, peripheral blood, and synovial tissue. Studies in mice have reported the role of B cells in osteoclast differentiation. More recently, plasma cell-derived RANKL has been shown to be involved in the development of periarticular bone loss in rheumatoid arthritis.

3.2.4. Effects of Synovial Fibroblasts on Osteoarticular Destruction

26Various factors in the synovial membrane are involved in RA pathogenesis. In particular, fibroblast-like synoviocytes (FLSs) are remarkably increased. FLSs are stacked in layers to form the inflammatory granulation tissue referred to as pannus. At the interface between the pannus and cartilage, the protease, such as MMP1, is overproduced and is involved in cartilage destruction. The pannus also plays an important role in osteoclast differentiation, as it overproduces RANKL, causing osteoarticular destruction. Furthermore, it also produces Wnt5a, which promotes osteoclast differentiation. The expression of Wnt5a in FLS induces inflammatory cytokines, which activate FLS itself. Recent studies using single-cell analysis have shown that cells in the blood, such as macrophages and lymphocytes, are main sources of TNF-α in the synovium of patients with RA. Activated FLSs produce IL-6, chemokines, and pro-angiogenic factors, which further increase blood cells that flow into the synovium and provoke a vicious cycle, comprising aggravation of inflammation and promotion of osteoclast differentiation.

27Additionally, the results of single-cell analysis have revealed various fibroblast subtypes. Mizoguchi et al. separated synovial fibroblasts into three subpopulations based on cell surface markers. Among these subpopulations, they have shown that Thy1-positive cells produce RANKL, MMP1, and MMP3 and that they form a synovial fibroblast subset contributing to articular destruction. The subsequent report demonstrated functional differences in fibroblasts with and without Thy1 in vivo. Furthermore, Wei et al. have reported that vascular endothelial cell-derived Notch signaling controls synovial fibroblast positional identity or characters that contribute to articular destruction (Figure 2). While current RA treatments primarily target inflammatory cytokines, therapeutic strategies targeting synovial fibroblasts and vascular endothelial cells directly are expected to be developed. Fibroblast differentiation is regulated by morphogens from active local microenvironments. Morphogens are conserved signaling molecules that induce the fate and function of specific cells and include Hedgehog, Wnt, Notch, and TGF-β molecules. Previously, we have reported that Wnt5a expressed in synovial fibroblasts regulates the differentiation and function of osteoclasts and is involved in osteoarticular destruction. The role of Wnt5a in the regulation of differentiation of synovial fibroblasts themselves warrants further studies.

4. Effects of RA Treatment on Bone Metabolism

28As described above, inflammatory cytokines, such as TNF-α and IL-6, promote RANKL expression in the synovial tissue in RA. RANKL-independent osteoclast-like cells induced by TNF-α and IL-6 under RA condition have been found recently. Moreover, TNF-α increases the expression of DKK1, which systemically inhibits osteogenesis. There is a large number of different drug groups that are generally used in RA. These facts suggest that the treatment of RA with biological disease-modifying antirheumatic drugs (bDMARDs) and janus kinase (JAK) inhibitors have effects on bone metabolism. In fact, a meta-analysis to see the relationship between the use of bDMARDs and progression of bone erosion in patients with RA has reported that most bDMARDs prevented decreases in modified Total Sharp Score. Findings on the effects of therapeutic intervention against RA on bone metabolism from preclinical studies and on bone mineral density from clinical studies are reviewed in the subsequent subsections.

4.1.1. Preclinical Studies

29According to the guidelines, methotrexate (MTX) is positioned as an anchor drug in antirheumatic treatment. The effects of MTX on bone metabolism were studied even earlier, and MTX has been reported to prevent decreased osteogenesis and increased bone resorption, thereby maintaining bone mineral density in arthritis model animals. It has been shown that MTX directly inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors. In a recent study, MTX was used as a control for bDMARDs and has been shown to suppress the production of inflammatory cytokines and increase the bone mineral density compared to those in untreated arthritis model animals.

4.1.2. Clinical Studies

30MTX, which has originally been used as an anticancer agent, has been reported to reduce bone mass at high doses. Effects of low-dose MTX on bone mass in patients with RA have also been reported; bone mineral densities in the proximal femur and lumbar vertebrae did not change after long-term use (Table 1). The discrepancy between the increased bone mineral density in model animals and the unchanged bone mineral density in humans requires further studies.

4.2.1. Preclinical Studies

31In the CIA model, TNF-α inhibition has been shown to mitigate bone erosion of joints, systemic bone mass reduction, and synovitis.

4.2.2. Clinical Studies

32Vis et al. analyzed bone mineral densities in 36 patients with RA who underwent infliximab (IFX] treatment for one year and have reported preserved bone mass in the hip joints and increased bone mass in the lumbar vertebrae. Furthermore, the same research group reported another study in 102 patients with RA who underwent IFX treatment for one year and has found that the bone mineral density in the metacarpal bone was decreased, whereas the bone mineral densities in the lumbar vertebrae and hip joints remained unchanged. Marotte et al. compared bone mineral densities after one year between 90 patients with RA who underwent IFX treatment and 99 patients with RA who did not. The bone mass levels in the femoral neck and lumbar vertebrae in the IFX-treated patient group were maintained compared with those in the untreated patient group. Chopin et al. also investigated the bone mineral densities in the lumbar vertebrae and the entire hip after 6 months and 12 months in 48 female patients with RA who underwent IFX treatment to show that it prevented bone mass decrease. Furthermore, in an analysis of 52 patients with RA who underwent IFX treatment for at least 2 years, Eekman et al. have shown that the bone mass in the metacarpal bone was reduced, whereas bone mineral densities in the lumbar vertebrae and hip joints were maintained (Table 1).

33Wijbrandts et al. investigated bone mineral densities in 46 patients with RA who underwent adalimumab (ADA) treatment. They compared the bone mineral density of the femur at the time of ADA treatment initiation with that measured 1 year after initiation, and they noted the possibility that ADA treatment prevented bone mass decrease. Krieckaert et al. conducted a study in 184 patients with RA who underwent ADA treatment for at least 1 year and have reported that loss of bone mineral density in the spine was arrested over 4 years of ADA treatment, whereas bone mineral densities of the hand and hip continued to decrease after 1 and 4 years, respectively (Table 1).

34Gulyás et al. studied changes in bone mineral density in 36 patients with RA treated with etanercept (ETN) or certolizumab pegol (CZP) for one year. The results demonstrated that the 1-year anti-TNF treatment was effective for maintaining bone mineral density in the femoral neck and lumbar vertebrae (Table 1). Many reports, including those cited above, have shown that the use of TNF-α inhibitors in RA can maintain bone mineral densities in the hip joints and lumbar vertebrae. However, in a study on short-term effects of the TNF-α inhibition on bone mineral density, Orsolini et al. evaluated bone mineral densities in the femoral neck and lumbar vertebrae after 6 months in 54 patients with RA who underwent the TNF-α inhibition therapy with IFX, ADA, ETN, CZP, and golimumab, showing significant decreases in the femoral neck bone mineral density. The decreases were attributed to elevated osteogenic and resorption markers, which indicate that treatment with TNF-α inhibitors leads to a high bone turnover (Table 1). Possible problems of this study include a shorter study period (6 months) than other studies and heterogeneity of the study population.

4.3.1. Preclinical Studies

35IL-6 transgenic mice have increased osteoclasts and decreased bone mass compared to wild-type mice. However, in IL-6 knockout mice, the osteoclast apoptosis is promoted, and bone mass is increased. Furthermore, studies of anti-IL-6 receptor antibodies administered to the CIA model have shown an increased bone mineral density in the foot region, suppressed bone mass decrease in the femur and lumbar vertebrae, and decreased bone resorption markers.

4.3.2. Clinical Studies

36Abu-Shakra et al. investigated the rates of change from baseline in the bone mineral density after 96 weeks in 145 patients with RA who underwent the tocilizumab (TCZ) treatment. The bone mineral densities in the lumbar vertebrae, femoral neck, and entire hip were maintained. Kume et al. analyzed bone mineral densities in the lumbar vertebrae and proximal femur after 52 weeks in patients with RA who underwent the TCZ treatment. The bone mineral densities in both sites increased in patients whose bone mass was decreased originally. Briot et al. have reported rates of change over 48 weeks in 103 patients with RA who underwent TCZ treatment, showing no changes in the bone mineral density in both the hip joints and lumbar vertebrae. Interestingly, the serum DKK1 level was significantly decreased from baseline, and osteogenic markers significantly increased (Table 1). Regarding the use of IL-6 inhibitors in patients with RA, the REBONE study, in which HR-pQCT was used to analyze bone erosions in fingers, compared bone erosions in the metacarpal and distal radius after 1 year between 33 patients treated with TCZ and 33 patients treated with ADA + MTX. The bone erosions in the TCZ group were not only decreased in number but also repaired significantly compared with those in the ADA + MTX group. This report combined with the report by Briot et al. suggests that IL-6 inhibition in RA promotes osteogenesis through decrease in DKK1. In addition, DKK1 is thought to be involved in pannus angiogenesis, and serum DKK1 correlates with the severity of joint destruction. DKK1 has the potential to be a biomarker for rheumatoid arthritis, and treatments targeting IL-6 that reduce DKK1 are promising.

37Several clinical studies have shown that sarilumab treatment reduced the serum RANKL level. In one of these studies, similar to TCZ, osteogenic marker levels were analyzed and found to be elevated compared to those in the control group (Table 1). However, the relationship between serum DKK1 level and bone mineral density still remains to be analyzed in future studies.

4.4.1. Preclinical Studies

38T cells are activated by co-stimulation with antigen-presenting cells. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) Ig (abatacept: ABT) binds to CD80/CD86 on the surface of antigen-presenting cells and inhibits CD28 co-stimulation signaling, thereby hampering T cell activation. In an experiment, in which ABT was administered to healthy mice, Roser-Page et al. have shown the increased bone mass by promoting bone formation due to anergized T-cell-dependent Wnt10b expression. On the other hand, in an experiment, in which ABT was administered to the RA model, Axmann et al. have shown T-cell-independent, direct deceleration of bone destruction. Furthermore, the same group analyzed the underlying mechanism of action in detail and have reported that ABT impedes osteoclast differentiation through the indoleamine 2,3-dioxygenase (IDO)-tryptophan pathway. Meanwhile, Okada et al. have demonstrated that ABT inhibits intracellular calcium oscillations depending on immunoglobulin-like receptors on osteoclasts and downregulates the NFATc1 expression in bone marrow macrophages, thereby hampering osteoclast differentiation.

4.4.2. Clinical Studies

39Tada et al. studied the effects of ABT on bone mineral density and bone metabolism markers in 165 patients with RA. The rate of increase in the bone mineral density over 48 weeks for the femoral neck in the ABT group was significantly higher than that in the non-ABT group; however, the rate for the lumbar vertebrae did not differ between the two groups (Table 1). These data suggest that ABT improves the femoral neck bone mineral density in patients with RA.

4.5.1. Preclinical Studies

40JAK inhibitors are low-molecular-weight compounds that inhibit the JAK family, a class of non-receptor tyrosine kinases that mediate signal transduction of inflammatory cytokines, such as interleukins and interferons. Among DMARDs, five JAK inhibitors classified as targeted synthetic DMARDs (tsDMARDs) are currently available for RA treatment.

41Tofacitinib (TOF) is a JAK1/2/3 inhibitor. TOF has been reported to suppress osteoarticular destruction in adjuvant arthritis model rats. In vitro studies have shown that TOF does not interfere with the differentiation and function of human osteoclasts induced by M-CSF and RANKL, but it suppresses RANKL production by T lymphocytes. In contrast, TOF has been reported to impede the differentiation of human osteoclast-like cells induced by M-CSF, TNF-α, and IL-6. TOF has also been shown to promote osteogenesis through promotion of differentiation from mesenchymal stem cells to osteoblasts and activation of the canonical Wnt pathway in osteoblasts.

42Baricitinib (BAR) is a JAK1/2 inhibitor. BAR has been shown to suppress osteoarticular destruction in arthritis model rats and mice. BAR has also been reported to indirectly inhibit osteoclast differentiation through the suppression of RANKL expression on osteoblasts in a mouse osteoclast co-culture system; however, BAR does not directly inhibit osteoclast differentiation. Furthermore, similar to TOF, BAR has also been shown to promote osteogenesis through activation of the canonical Wnt pathway in osteoblasts.

43Peficitinib (PEF) is an inhibitor of JAK1/2/3 and Tyrosine kinase 2. PEF has been reported to suppress osteoarticular destruction in adjuvant arthritis model rats; however, the effects of PEF on bone metabolism have not been studied.

44Filgotinib (FIL) is a preferential JAK1 inhibitor. FIL has been reported to suppress osteoarticular destruction in CIA model mice. The decreased RANKL gene expression in the extremities has been demonstrated in the FIL-treated group. A detailed analysis of effects of upadacitinib (UPA), another preferential JAK1 inhibitor, on bone metabolism has not been reported.

45The effects of respective JAK inhibitors on Foxm1-positive osteoclasts and DC-OCs that emerge under the RA condition are interesting.

4.5.2. Clinical Studies

46Hamar et al. have reported the effects of TOF administration in 30 patients with RA. According to their report, 1-year TOF administration preserved bone mineral densities in the lumbar vertebrae and femoral neck. Osteogenic markers were elevated, and bone resorption markers were reduced due to increased OPG (Table 1).

47The excellent clinical results and bone-erosion-reducing effects with BAR have been reported. Thudium et al. conducted a subgroup analysis of the RA-BUILD study and have reported changes in bone metabolism markers in 240 subjects. After 12 weeks of the BAR treatment, osteogenic markers did not change significantly, whereas bone resorption markers were significantly reduced. The bone mineral density was not analyzed (Table 1).

48PEF, FIL, and UPA have been shown to improve the modified Total Sharp Score in various clinical studies; however, analyses of bone metabolism markers and changes in the bone mineral density are yet to be conducted. Respective drugs inhibit different types of JAK. We hope that the effects of respective drugs on bone metabolism will be evaluated, and evidence-based selection of drugs will be discussed in the future.

4.6. Other Treatments

49In recent years, the usefulness of phytopharmaceuticals, such as alisol-B, resveratrol, and arctigenin, has been reported in the area of bone metabolism as an innovative adjuvant therapy. Resveratrol, in particular, promotes osteoblast differentiation of mesenchymal stem cells. The kind of action these medicines have on inflammation and bone metabolism warrants further research.

5. Conclusions

50We reviewed bone metabolism under physiological and RA conditions, and described the effects of therapeutic intervention against RA on the bone. Many reports have documented that bDMARDs and JAK inhibitors preserve or increase the bone mineral density. However, no consensus has been reached as to whether the preservation of the bone mineral density with bDMARDs treatments results in a reduced incidence rate of fractures. Some studies have reported that bDMARDs prevented the bone mineral density from decreasing, but they did not reduce the incidence of fractures, whereas some other studies have reported that they reduced the incidence of fractures. Completely different mechanisms underlie local bone destruction in RA and systemic osteoporosis. Therefore, as a prerequisite to discuss whether the use of bDMARDs in patients with RA reduces the incidence of fractures, the patients must undergo an appropriate therapeutic intervention against osteoporosis. Furthermore, drug effects on bone quality and bone mass are important points to consider while selecting drugs for the treatment of osteoporosis in patients with RA.

References 208

1.
Smolen J.S., Aletaha D., Barton A., Burmester G.R., Emery P., Firestein G.S., Kavanaugh A., McInnes I.B., Solomon D.H., Strand V., et al. Rheumatoid arthritis. Nat. Rev. Dis. Primers. 2018;4:18001.
Not in our library10.1038/nrdp.2018.1
2.
Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies · 2018
No notice
3.
Nakajima A., Sakai R., Inoue E., Harigai M. Prevalence of patients with rheumatoid arthritis and age-stratified trends in clinical characteristics and treatment, based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Int. J. Rheum. Dis. 2020;23:1676-1684.
Not in our library10.1111/1756-185x.13974
4.
Goldring S.R. Inflammatory signaling induced bone loss. Bone. 2015;80:143-149.
Not in our library10.1016/j.bone.2015.05.024
5.
Okamoto K., Takayanagi H. Osteoimmunology. Cold Spring Harb. Perspect. Med. 2019;9:a031245.
Not in our library10.1101/cshperspect.a031245
6.
Emery P., Smolen J.S., Ganguli A., Meerwein S., Bao Y., Kupper H., Chen N., Kavanaugh A. Effect of adalimumab on the work-related outcomes scores in patients with early rheumatoid arthritis receiving methotrexate. Rheumatology. 2016;55:1458-1465.
Not in our library10.1093/rheumatology/kew056
7.
Takeuchi T., Nakajima R., Komatsu S., Yamazaki K., Nakamura T., Agata N., Igarashi A., Tango T., Tanaka Y. Impact of Adalimumab on Work Productivity and Activity Impairment in Japanese Patients with Rheumatoid Arthritis: Large-Scale, Prospective, Single-Cohort ANOUVEAU Study. Adv. Ther. 2017;34:686-702.
Not in our library10.1007/s12325-017-0477-z
8.
Tanaka Y., Kameda H., Saito K., Kaneko Y., Tanaka E., Yasuda S., Tamura N., Fujio K., Fujii T., Kojima T., et al. Effect of subcutaneous tocilizumab treatment on work/housework status in biologic-naïve rheumatoid arthritis patients using inverse probability of treatment weighting: FIRST ACT-SC study. Arthritis Res. Ther. 2018;20:151.
Not in our library10.1186/s13075-018-1647-3
9.
Michaud K., Pope J.E., Emery P., Zhu B., Gaich C.L., DeLozier A.M., Zhang X., Dickson C.L., Smolen J.S. Relative Impact of Pain and Fatigue on Work Productivity in Patients with Rheumatoid Arthritis from the RA-BEAM Baricitinib Trial. Rheumatol. Ther. 2019;6:409-419.
Not in our library10.1007/s40744-019-0164-4
10.
Smolen J.S., Landewé R.B.M., Bijlsma J.W.J., Burmester G.R., Dougados M., Kerschbaumer A., McInnes I.B., Sepriano A., van Vollenhoven R.F., de Wit M., et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 2020;79:685-699.
Not in our library10.1136/annrheumdis-2019-216655
11.
Van der Heijde D.M. Plain X-rays in rheumatoid arthritis: Overview of scoring methods, their reliability and applicability. Bailliere’s Clin. Rheumatol. 1996;10:435-453.
Not in our library10.1016/s0950-3579(96)80043-4
12.
Fries J.F., Spitz P., Kraines R.G., Holman H.R. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23:137-145.
Not in our library10.1002/art.1780230202
13.
Danks L., Komatsu N., Guerrini M.M., Sawa S., Armaka M., Kollias G., Nakashima T., Takayanagi H. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann. Rheum. Dis. 2016;75:1187-1195.
Not in our library10.1136/annrheumdis-2014-207137
14.
Wang X., Xia S., Fu B. RNA-seq analysis of synovial fibroblasts in human rheumatoid arthritis. Mol. Med. Rep. 2014;10:241-247.
Not in our library10.3892/mmr.2014.2182
15.
Malemud C.J. Matrix Metalloproteinases and Synovial Joint Pathology. Prog. Mol. Biol. Transl. Sci. 2017;148:305-325.
Not in our library10.1016/bs.pmbts.2017.03.003
16.
Nishimura R., Hata K., Takahata Y., Murakami T., Nakamura E., Ohkawa M., Ruengsinpinya L. Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases. Int. J. Mol. Sci. 2020;21:1340.
Not in our library10.3390/ijms21041340
17.
Robling A.G., Bonewald L.F. The Osteocyte: New Insights. Annu. Rev. Physiol. 2020;82:485-506.
Not in our library10.1146/annurev-physiol-021119-034332
18.
Takashi Y., Fukumoto S. Phosphate-sensing and regulatory mechanism of FGF23 production. J. Endocrinol. Investig. 2020;43:877-883.
Not in our library10.1007/s40618-020-01205-9
19.
Manolagas S.C., Parfitt A.M. What old means to bone. Trends Endocrinol. Metab. 2010;21:369-374.
Not in our library10.1016/j.tem.2010.01.010
20.
Sims N.A., Martin T.J. Osteoclasts Provide Coupling Signals to Osteoblast Lineage Cells Through Multiple Mechanisms. Annu. Rev. Physiol. 2020;82:507-529.
Not in our library10.1146/annurev-physiol-021119-034425
21.
Udagawa N., Koide M., Nakamura M., Nakamichi Y., Yamashita T., Uehara S., Kobayashi Y., Furuya Y., Yasuda H., Fukuda C., et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J. Bone Miner. Metab. 2021;39:19-26.
Not in our library10.1007/s00774-020-01162-6
22.
MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-β signalling in osteoblasts · 2017
Not checked
23.
Ducy P., Zhang R., Geoffroy V., Ridall A.L., Karsenty G. Osf2/Cbfa1: A transcriptional activator of osteoblast differentiation. Cell. 1997;89:747-754.
Not in our library10.1016/s0092-8674(00)80257-3
24.
Komori T., Yagi H., Nomura S., Yamaguchi A., Sasaki K., Deguchi K., Shimizu Y., Bronson R.T., Gao Y.H., Inada M., et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755-764.
Not in our library10.1016/s0092-8674(00)80258-5
25.
Komori T. Molecular Mechanism of Runx2-Dependent Bone Development. Mol. Cells. 2020;43:168-175.
Not in our library10.14348/molcells.2019.0244
26.
Nakashima K., Zhou X., Kunkel G., Zhang Z., Deng J.M., Behringer R.R., de Crombrugghe B. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108:17-29.
Not in our library10.1016/s0092-8674(01)00622-5
27.
Baron R., Kneissel M. WNT signaling in bone homeostasis and disease: From human mutations to treatments. Nat. Med. 2013;19:179-192.
Not in our library10.1038/nm.3074
28.
Maeda K., Takahashi N., Kobayashi Y. Roles of Wnt signals in bone resorption during physiological and pathological states. J. Mol. Med. 2013;91:15-23.
Not in our library10.1007/s00109-012-0974-0
29.
Katagiri T., Watabe T. Bone Morphogenetic Proteins. Cold Spring Harb. Perspect. Biol. 2016;8:a021899.
Not in our library10.1101/cshperspect.a021899
30.
Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions · 2020
No notice
31.
Wang F., Tarkkonen K., Nieminen-Pihala V., Nagano K., Majidi R.A., Puolakkainen T., Rummukainen P., Lehto J., Roivainen A., Zhang F.P., et al. Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation. J. Bone Miner. Res. 2019;34:1129-1142.
Not in our library10.1002/jbmr.3680
32.
Wang F., Rummukainen P., Heino T.J., Kiviranta R. Osteoblastic Wnt1 regulates periosteal bone formation in adult mice. Bone. 2021;143:115754.
Not in our library10.1016/j.bone.2020.115754
33.
Bennett C.N., Longo K.A., Wright W.S., Suva L.J., Lane T.F., Hankenson K.D., MacDougald O.A. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc. Natl. Acad. Sci. USA. 2005;102:3324-3329.
Not in our library10.1073/pnas.0408742102
34.
Bennett C.N., Ouyang H., Ma Y.L., Zeng Q., Gerin I., Sousa K.M., Lane T.F., Krishnan V., Hankenson K.D., MacDougald O.A. Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J. Bone Miner. Res. 2007;22:1924-1932.
Not in our library10.1359/jbmr.070810
35.
WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders · 2020
Not checked
36.
Cawthorn W.P., Bree A.J., Yao Y., Du B., Hemati N., Martinez-Santibanez G., MacDougald O.A. Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a beta-catenin-dependent mechanism. Bone. 2012;50:477-489.
Not in our library10.1016/j.bone.2011.08.010
37.
Gao Y., Patil S., Jia J. The Development of Molecular Biology of Osteoporosis. Int. J. Mol. Sci. 2021;22:8182.
Not in our library10.3390/ijms22158182
38.
Nakanishi R., Akiyama H., Kimura H., Otsuki B., Shimizu M., Tsuboyama T., Nakamura T. Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass. J. Bone Miner. Res. 2008;23:271-277.
Not in our library10.1359/jbmr.071007
39.
Yao W., Cheng Z., Shahnazari M., Dai W., Johnson M.L., Lane N.E. Overexpression of secreted frizzled-related protein 1 inhibits bone formation and attenuates parathyroid hormone bone anabolic effects. J. Bone Miner. Res. 2010;25:190-199.
Not in our library10.1359/jbmr.090719
40.
Yamada A., Iwata T., Yamato M., Okano T., Izumi Y. Diverse functions of secreted frizzled-related proteins in the osteoblastogenesis of human multipotent mesenchymal stromal cells. Biomaterials. 2013;34:3270-3278.
Not in our library10.1016/j.biomaterials.2013.01.066
41.
Nakashima T., Hayashi M., Fukunaga T., Kurata K., Oh-Hora M., Feng J.Q., Bonewald L.F., Kodama T., Wutz A., Wagner E.F., et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 2011;17:1231-1234.
Not in our library10.1038/nm.2452
42.
Xiong J., Onal M., Jilka R.L., Weinstein R.S., Manolagas S.C., O’Brien C.A. Matrix-embedded cells control osteoclast formation. Nat. Med. 2011;17:1235-1241.
Not in our library10.1038/nm.2448
43.
Powell W.F., Barry K.J., Tulum I., Kobayashi T., Harris S.E., Bringhurst F.R., Pajevic P.D. Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J. Endocrinol. 2011;209:21-32.
Not in our library10.1530/joe-10-0308
44.
Delgado-Calle J., Tu X., Pacheco-Costa R., McAndrews K., Edwards R., Pellegrini G.G., Kuhlenschmidt K., Olivos N., Robling A., Peacock M., et al. Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor. J. Bone Miner. Res. 2017;32:522-535.
Not in our library10.1002/jbmr.3011
45.
Bonnet N., Conway S.J., Ferrari S.L. Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin. Proc. Natl. Acad. Sci. USA. 2012;109:15048-15053.
Not in our library10.1073/pnas.1203085109
46.
Bonnet N., Standley K.N., Bianchi E.N., Stadelmann V., Foti M., Conway S.J., Ferrari S.L. The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity. J. Biol. Chem. 2009;284:35939-35950.
Not in our library10.1074/jbc.m109.060335
47.
Walker E.C., McGregor N.E., Poulton I.J., Solano M., Pompolo S., Fernandes T.J., Constable M.J., Nicholson G.C., Zhang J.G., Nicola N.A., et al. Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J. Clin. Investig. 2010;120:582-592.
Not in our library10.1172/jci40568
48.
Koide M., Kobayashi Y., Yamashita T., Uehara S., Nakamura M., Hiraoka B.Y., Ozaki Y., Iimura T., Yasuda H., Takahashi N., et al. Bone Formation Is Coupled to Resorption Via Suppression of Sclerostin Expression by Osteoclasts. J. Bone Min. Res. 2017;32:2074-2086.
Not in our library10.1002/jbmr.3175
49.
Koide M., Kobayashi Y. Regulatory mechanisms of sclerostin expression during bone remodeling. J. Bone Min. Metab. 2019;37:9-17.
Not in our library10.1007/s00774-018-0971-7
50.
Udagawa N., Takahashi N., Akatsu T., Tanaka H., Sasaki T., Nishihara T., Koga T., Martin T.J., Suda T. Origin of osteoclasts: Mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl. Acad. Sci. USA. 1990;87:7260-7264.
Not in our library10.1073/pnas.87.18.7260
51.
Takahashi N., Akatsu T., Udagawa N., Sasaki T., Yamaguchi A., Moseley J.M., Martin T.J., Suda T. Osteoblastic cells are involved in osteoclast formation. Endocrinology. 1988;123:2600-2602.
Not in our library10.1210/endo-123-5-2600
52.
Suda T., Takahashi N., Udagawa N., Jimi E., Gillespie M.T., Martin T.J. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev. 1999;20:345-357.
Not in our library10.1210/edrv.20.3.0367
53.
Naito A., Azuma S., Tanaka S., Miyazaki T., Takaki S., Takatsu K., Nakao K., Nakamura K., Katsuki M., Yamamoto T., et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells Devoted Mol. Cell. Mech. 1999;4:353-362.
Not in our library10.1046/j.1365-2443.1999.00265.x
54.
Lomaga M.A., Yeh W.C., Sarosi I., Duncan G.S., Furlonger C., Ho A., Morony S., Capparelli C., Van G., Kaufman S., et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999;13:1015-1024.
Not in our library10.1101/gad.13.8.1015
55.
Walsh M.C., Lee J., Choi Y. Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol. Rev. 2015;266:72-92.
Not in our library10.1111/imr.12302
56.
Ishida N., Hayashi K., Hoshijima M., Ogawa T., Koga S., Miyatake Y., Kumegawa M., Kimura T., Takeya T. Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J. Biol. Chem. 2002;277:41147-41156.
Not in our library10.1074/jbc.m205063200
57.
Takayanagi H., Kim S., Koga T., Nishina H., Isshiki M., Yoshida H., Saiura A., Isobe M., Yokochi T., Inoue J., et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell. 2002;3:889-901.
Not in our library10.1016/s1534-5807(02)00369-6
58.
Kukita T., Wada N., Kukita A., Kakimoto T., Sandra F., Toh K., Nagata K., Iijima T., Horiuchi M., Matsusaki H., et al. RANKL-induced DC-STAMP is essential for osteoclastogenesis. J. Exp. Med. 2004;200:941-946.
Not in our library10.1084/jem.20040518
59.
Yagi M., Miyamoto T., Sawatani Y., Iwamoto K., Hosogane N., Fujita N., Morita K., Ninomiya K., Suzuki T., Miyamoto K., et al. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J. Exp. Med. 2005;202:345-351.
Not in our library10.1084/jem.20050645
60.
Inaoka T., Bilbe G., Ishibashi O., Tezuka K., Kumegawa M., Kokubo T. Molecular cloning of human cDNA for cathepsin K: Novel cysteine proteinase predominantly expressed in bone. Biochem. Biophys. Res. Commun. 1995;206:89-96.
Not in our library10.1006/bbrc.1995.1013
61.
Koga T., Inui M., Inoue K., Kim S., Suematsu A., Kobayashi E., Iwata T., Ohnishi H., Matozaki T., Kodama T., et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 2004;428:758-763.
Not in our library10.1038/nature02444
62.
Nakamura M., Udagawa N., Matsuura S., Mogi M., Nakamura H., Horiuchi H., Saito N., Hiraoka B.Y., Kobayashi Y., Takaoka K., et al. Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption. Endocrinology. 2003;144:5441-5449.
Not in our library10.1210/en.2003-0717
63.
Lotinun S., Kiviranta R., Matsubara T., Alzate J.A., Neff L., Luth A., Koskivirta I., Kleuser B., Vacher J., Vuorio E., et al. Osteoclast-specific cathepsin K deletion stim.mulates S1P-dependent bone formation. J. Clin. Investig. 2013;123:666-681.
Not in our library10.1172/jci64840
64.
Zhao C., Irie N., Takada Y., Shimoda K., Miyamoto T., Nishiwaki T., Suda T., Matsuo K. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab. 2006;4:111-121.
Not in our library10.1016/j.cmet.2006.05.012
65.
Takeshita S., Fumoto T., Matsuoka K., Park K.A., Aburatani H., Kato S., Ito M., Ikeda K. Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J. Clin. Investig. 2013;123:3914-3924.
Not in our library10.1172/jci69493
66.
Purdue P.E., Crotti T.N., Shen Z., Swantek J., Li J., Hill J., Hanidu A., Dimock J., Nabozny G., Goldring S.R., et al. Comprehensive profiling analysis of actively resorbing osteoclasts identifies critical signaling pathways regulated by bone substrate. Sci. Rep. 2014;4:7595.
Not in our library10.1038/srep07595
67.
Matsuoka K., Park K.A., Ito M., Ikeda K., Takeshita S. Osteoclast-derived complement component 3a stimulates osteoblast differentiation. J. Bone Miner. Res. 2014;29:1522-1530.
Not in our library10.1002/jbmr.2187
68.
Weivoda M.M., Ruan M., Pederson L., Hachfeld C., Davey R.A., Zajac J.D., Westendorf J.J., Khosla S., Oursler M.J. Osteoclast TGF-beta Receptor Signaling Induces Wnt1 Secretion and Couples Bone Resorption to Bone Formation. J. Bone Miner. Res. 2016;31:76-85.
Not in our library10.1002/jbmr.2586
69.
Ota K., Quint P., Ruan M., Pederson L., Westendorf J.J., Khosla S., Oursler M.J. TGF-beta induces Wnt10b in osteoclasts from female mice to enhance coupling to osteoblasts. Endocrinology. 2013;154:3745-3752.
Not in our library10.1210/en.2013-1272
70.
Pederson L., Ruan M., Westendorf J.J., Khosla S., Oursler M.J. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc. Natl. Acad. Sci. USA. 2008;105:20764-20769.
Not in our library10.1073/pnas.0805133106
71.
Walker E.C., McGregor N.E., Poulton I.J., Pompolo S., Allan E.H., Quinn J.M., Gillespie M.T., Martin T.J., Sims N.A. Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J. Bone Miner. Res. 2008;23:2025-2032.
Not in our library10.1359/jbmr.080706
72.
Xie H., Cui Z., Wang L., Xia Z., Hu Y., Xian L., Li C., Xie L., Crane J., Wan M., et al. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat. Med. 2014;20:1270-1278.
Not in our library10.1038/nm.3668
73.
Ikebuchi Y., Aoki S., Honma M., Hayashi M., Sugamori Y., Khan M., Kariya Y., Kato G., Tabata Y., Penninger J.M., et al. Coupling of bone resorption and formation by RANKL reverse signalling. Nature. 2018;561:195-200.
Not in our library10.1038/s41586-018-0482-7
74.
Redlich K., Smolen J.S. Inflammatory bone loss: Pathogenesis and therapeutic intervention. Nat. Rev. Drug Discov. 2012;11:234-250.
Not in our library10.1038/nrd3669
75.
Tanaka Y. Managing Osteoporosis and Joint Damage in Patients with Rheumatoid Arthritis: An Overview. J. Clin. Med. 2021;10:1241.
Not in our library10.3390/jcm10061241
76.
Tsukasaki M., Takayanagi H. Osteoimmunology: Evolving concepts in bone-immune interactions in health and disease. Nat. Rev. Immunol. 2019;19:626-642.
Not in our library10.1038/s41577-019-0178-8
77.
Chotiyarnwong P., McCloskey E.V. Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat. Rev. Endocrinol. 2020;16:437-447.
Not in our library10.1038/s41574-020-0341-0
78.
Charoenngam N. Vitamin D and Rheumatic Diseases: A Review of Clinical Evidence. Int. J. Mol. Sci. 2021;22:10659.
Not in our library10.3390/ijms221910659
79.
Adami G., Saag K.G. Osteoporosis Pathophysiology, Epidemiology, and Screening in Rheumatoid Arthritis. Curr. Rheumatol. Rep. 2019;21:34.
Not in our library10.1007/s11926-019-0836-7
80.
The Role of NF-κB in Physiological Bone Development and Inflammatory Bone Diseases: Is NF-κB Inhibition “Killing Two Birds with One Stone”? · 2019
No notice
81.
Berardi S., Corrado A., Maruotti N., Cici D., Cantatore F.P. Osteoblast role in the pathogenesis of rheumatoid arthritis. Mol. Biol. Rep. 2021;48:2843-2852.
Not in our library10.1007/s11033-021-06288-y
82.
Diarra D., Stolina M., Polzer K., Zwerina J., Ominsky M.S., Dwyer D., Korb A., Smolen J., Hoffmann M., Scheinecker C., et al. Dickkopf-1 is a master regulator of joint remodeling. Nat. Med. 2007;13:156-163.
Not in our library10.1038/nm1538
83.
Tsukasaki M., Yamada A., Suzuki D., Aizawa R., Miyazono A., Miyamoto Y., Suzawa T., Takami M., Yoshimura K., Morimura N., et al. Expression of POEM, a positive regulator of osteoblast differentiation, is suppressed by TNF-α. BioChem. Biophys. Res. Commun. 2011;410:766-770.
Not in our library10.1016/j.bbrc.2011.06.048
84.
Qin Z., Fang Z., Zhao L., Chen J., Li Y., Liu G. High dose of TNF-α suppressed osteogenic differentiation of human dental pulp stem cells by activating the Wnt/β-catenin signaling. J. Mol. Histol. 2015;46:409-420.
Not in our library10.1007/s10735-015-9630-7
85.
Sun Z., Yan K., Liu S., Yu X., Xu J., Liu J., Li S. Semaphorin 3A promotes the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells in inflammatory environments by suppressing the Wnt/β-catenin signaling pathway. J. Mol. Histol. 2021;52:1245-1255.
Not in our library10.1007/s10735-020-09941-1
86.
Glass D.A., Bialek P., Ahn J.D., Starbuck M., Patel M.S., Clevers H., Taketo M.M., Long F., McMahon A.P., Lang R.A., et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev. Cell. 2005;8:751-764.
Not in our library10.1016/j.devcel.2005.02.017
87.
Colditz J., Thiele S., Baschant U., Niehrs C., Bonewald L.F., Hofbauer L.C., Rauner M. Postnatal Skeletal Deletion of Dickkopf-1 Increases Bone Formation and Bone Volume in Male and Female Mice, Despite Increased Sclerostin Expression. J. Bone Miner. Res. 2018;33:1698-1707.
Not in our library10.1002/jbmr.3463
88.
Stach C.M., Bäuerle M., Englbrecht M., Kronke G., Engelke K., Manger B., Schett G. Periarticular bone structure in rheumatoid arthritis patients and healthy individuals assessed by high-resolution computed tomography. Arthritis Rheum. 2010;62:330-339.
Not in our library10.1002/art.27252
89.
Zhu T.Y., Griffith J.F., Qin L., Hung V.W., Fong T.N., Au S.K., Li M., Lam Y.Y., Wong C.K., Kwok A.W., et al. Alterations of bone density, microstructure, and strength of the distal radius in male patients with rheumatoid arthritis: A case-control study with HR-pQCT. J. Bone Miner. Res. 2014;29:2118-2129.
Not in our library10.1002/jbmr.2221
90.
Yamanaka H., Sugiyama N., Inoue E., Taniguchi A., Momohara S. Estimates of the prevalence of and current treatment practices for rheumatoid arthritis in Japan using reimbursement data from health insurance societies and the IORRA cohort (I). Mod. Rheumatol. 2014;24:33-40.
Not in our library10.3109/14397595.2013.854059
91.
Komori T. Glucocorticoid Signaling and Bone Biology. Horm. Metab. Res. Horm.—Stoffwechs. Horm. Metab. 2016;48:755-763.
Not in our library10.1055/s-0042-110571
92.
Sasaki F., Hayashi M., Mouri Y., Nakamura S., Adachi T., Nakashima T. Mechanotransduction via the Piezo1-Akt pathway underlies Sost suppression in osteocytes. Biochem. Biophys. Res. Commun. 2020;521:806-813.
Not in our library10.1016/j.bbrc.2019.10.174
93.
Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-ß-catenin · 2020
No notice
94.
Sasaki F., Hayashi M., Ono T., Nakashima T. The regulation of RANKL by mechanical force. J. Bone Miner. Metab. 2021;39:34-44.
Not in our library10.1007/s00774-020-01145-7
95.
Lin J., Liu J., Davies M.L., Chen W. Serum Vitamin D Level and Rheumatoid Arthritis Disease Activity: Review and Meta-Analysis. PLoS ONE. 2016;11:e0146351.
Not in our library10.1371/journal.pone.0146351
96.
Lee Y.H., Bae S.C. Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: A meta-analysis. Clin. Exp. Rheumatol. 2016;34:827-833.
Not in our library
97.
Hasegawa T., Kikuta J., Sudo T., Matsuura Y., Matsui T., Simmons S., Ebina K., Hirao M., Okuzaki D., Yoshida Y., et al. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nat. Immunol. 2019;20:1631-1643.
Not in our library10.1038/s41590-019-0526-7
98.
Narisawa M., Kubo S., Okada Y., Yamagata K., Nakayamada S., Sakata K., Yamaoka K., Tanaka Y. Human dendritic cell-derived osteoclasts with high bone resorption capacity and T cell stimulation ability. Bone. 2021;142:115616.
Not in our library10.1016/j.bone.2020.115616
99.
Ranges G.E., Sriram S., Cooper S.M. Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4. J. Exp. Med. 1985;162:1105-1110.
Not in our library10.1084/jem.162.3.1105
100.
Okada Y., Wu D., Trynka G., Raj T., Terao C., Ikari K., Kochi Y., Ohmura K., Suzuki A., Yoshida S., et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506:376-381.
Not in our library10.1038/nature12873
101.
Kochi Y., Okada Y., Suzuki A., Ikari K., Terao C., Takahashi A., Yamazaki K., Hosono N., Myouzen K., Tsunoda T., et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat. Genet. 2010;42:515-519.
Not in our library10.1038/ng.583
102.
Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies · 2021
No notice
103.
Kremer J.M., Dougados M., Emery P., Durez P., Sibilia J., Shergy W., Steinfeld S., Tindall E., Becker J.C., Li T., et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:2263-2271.
Not in our library10.1002/art.21201
104.
Takayanagi H., Ogasawara K., Hida S., Chiba T., Murata S., Sato K., Takaoka A., Yokochi T., Oda H., Tanaka K., et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000;408:600-605.
Not in our library10.1038/35046102
105.
Sato K., Suematsu A., Okamoto K., Yamaguchi A., Morishita Y., Kadono Y., Tanaka S., Kodama T., Akira S., Iwakura Y., et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 2006;203:2673-2682.
Not in our library10.1084/jem.20061775
106.
Jovanovic D.V., Di Battista J.A., Martel-Pelletier J., Jolicoeur F.C., He Y., Zhang M., Mineau F., Pelletier J.P. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J. Immunol. 1998;160:3513-3521.
Not in our library
107.
Ogura H., Murakami M., Okuyama Y., Tsuruoka M., Kitabayashi C., Kanamoto M., Nishihara M., Iwakura Y., Hirano T. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity. 2008;29:628-636.
Not in our library10.1016/j.immuni.2008.07.018
108.
Sakaguchi S., Mikami N., Wing J.B., Tanaka A., Ichiyama K., Ohkura N. Regulatory T Cells and Human Disease. Annu. Rev. Immunol. 2020;38:541-566.
Not in our library10.1146/annurev-immunol-042718-041717
109.
Komatsu N., Okamoto K., Sawa S., Nakashima T., Oh-hora M., Kodama T., Tanaka S., Bluestone J.A., Takayanagi H. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 2014;20:62-68.
Not in our library10.1038/nm.3432
110.
Lubberts E., Koenders M.I., Oppers-Walgreen B., van den Bersselaar L., Coenen-de Roo C.J., Joosten L.A., van den Berg W.B. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 2004;50:650-659.
Not in our library10.1002/art.20001
111.
Kotake S., Udagawa N., Takahashi N., Matsuzaki K., Itoh K., Ishiyama S., Saito S., Inoue K., Kamatani N., Gillespie M.T., et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Investig. 1999;103:1345-1352.
Not in our library10.1172/jci5703
112.
Hirota K., Yoshitomi H., Hashimoto M., Maeda S., Teradaira S., Sugimoto N., Yamaguchi T., Nomura T., Ito H., Nakamura T., et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med. 2007;204:2803-2812.
Not in our library10.1084/jem.20071397
113.
Interleukin‐17–producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers · 2008
No notice
114.
Genovese M.C., Durez P., Richards H.B., Supronik J., Dokoupilova E., Mazurov V., Aelion J.A., Lee S.H., Codding C.E., Kellner H., et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: A phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann. Rheum. Dis. 2013;72:863-869.
Not in our library10.1136/annrheumdis-2012-201601
115.
Tlustochowicz W., Rahman P., Seriolo B., Krammer G., Porter B., Widmer A., Richards H.B. Efficacy and Safety of Subcutaneous and Intravenous Loading Dose Regimens of Secukinumab in Patients with Active Rheumatoid Arthritis: Results from a Randomized Phase II Study. J. Rheumatol. 2016;43:495-503.
Not in our library10.3899/jrheum.150117
116.
Mease P.J., Jeka S., Jaller J.J., Kitumnuaypong T., Louthrenoo W., Mann H., Matsievskaia G., Soriano E.R., Jia B., Wang C., et al. CNTO6785, a Fully Human Antiinterleukin 17 Monoclonal Antibody, in Patients with Rheumatoid Arthritis with Inadequate Response to Methotrexate: A Randomized, Placebo-controlled, Phase II, Dose-ranging Study. J. Rheumatol. 2018;45:22-31.
Not in our library10.3899/jrheum.161238
117.
Smolen J.S., Agarwal S.K., Ilivanova E., Xu X.L., Miao Y., Zhuang Y., Nnane I., Radziszewski W., Greenspan A., Beutler A., et al. A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann. Rheum. Dis. 2017;76:831-839.
Not in our library10.1136/annrheumdis-2016-209831
118.
Yago T., Nanke Y., Kawamoto M., Kobashigawa T., Yamanaka H., Kotake S. IL-23 and Th17 Disease in Inflammatory Arthritis. J. Clin. Med. 2017;6:81.
Not in our library10.3390/jcm6090081
119.
Taams L.S. Interleukin-17 in rheumatoid arthritis: Trials and tribulations. J. Exp. Med. 2020;217:e20192048.
Not in our library10.1084/jem.20192048
120.
Edwards J.C., Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology. 2001;40:205-211.
Not in our library10.1093/rheumatology/40.2.205
121.
Syversen S.W., Gaarder P.I., Goll G.L., Ødegård S., Haavardsholm E.A., Mowinckel P., van der Heijde D., Landewé R., Kvien T.K. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: Results from a 10-year longitudinal study. Ann. Rheum. Dis. 2008;67:212-217.
Not in our library10.1136/ard.2006.068247
122.
Harre U., Georgess D., Bang H., Bozec A., Axmann R., Ossipova E., Jakobsson P.J., Baum W., Nimmerjahn F., Szarka E., et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Investig. 2012;122:1791-1802.
Not in our library10.1172/jci60975
123.
Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss · 2015
No notice
124.
Negishi-Koga T., Gober H.J., Sumiya E., Komatsu N., Okamoto K., Sawa S., Suematsu A., Suda T., Sato K., Takai T., et al. Immune complexes regulate bone metabolism through FcRγ signalling. Nat. Commun. 2015;6:6637.
Not in our library10.1038/ncomms7637
125.
Rao D.A., Gurish M.F., Marshall J.L., Slowikowski K., Fonseka C.Y., Liu Y., Donlin L.T., Henderson L.A., Wei K., Mizoguchi F., et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542:110-114.
Not in our library10.1038/nature20810
126.
Yeo L., Toellner K.M., Salmon M., Filer A., Buckley C.D., Raza K., Scheel-Toellner D. Cytokine mRNA profiling identifies B cells as a major source of RANKL in rheumatoid arthritis. Ann. Rheum. Dis. 2011;70:2022-2028.
Not in our library10.1136/ard.2011.153312
127.
Ota Y., Niiro H., Ota S., Ueki N., Tsuzuki H., Nakayama T., Mishima K., Higashioka K., Jabbarzadeh-Tabrizi S., Mitoma H., et al. Generation mechanism of RANKL(+) effector memory B cells: Relevance to the pathogenesis of rheumatoid arthritis. Arthritis Res. Ther. 2016;18:67.
Not in our library10.1186/s13075-016-0957-6
128.
Meednu N., Zhang H., Owen T., Sun W., Wang V., Cistrone C., Rangel-Moreno J., Xing L., Anolik J.H. Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68:805-816.
Not in our library10.1002/art.39489
129.
Xu S., Zhang Y., Liu B., Li K., Huang B., Yan B., Zhang Z., Liang K., Jia C., Lin J., et al. Activation of mTORC1 in B Lymphocytes Promotes Osteoclast Formation via Regulation of β-Catenin and RANKL/OPG. J. Bone Miner. Res. 2016;31:1320-1333.
Not in our library10.1002/jbmr.2800
130.
Komatsu N., Win S., Yan M., Huynh N.C., Sawa S., Tsukasaki M., Terashima A., Pluemsakunthai W., Kollias G., Nakashima T., et al. Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis. J. Clin. Investig. 2021;131:e143060.
Not in our library10.1172/jci143060
131.
Maeda K., Kobayashi Y., Udagawa N., Uehara S., Ishihara A., Mizoguchi T., Kikuchi Y., Takada I., Kato S., Kani S., et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat. Med. 2012;18:405-412.
Not in our library10.1038/nm.2653
132.
MacLauchlan S., Zuriaga M.A., Fuster J.J., Cuda C.M., Jonason J., Behzadi F., Duffen J.P., Haines G.K., Aprahamian T., Perlman H., et al. Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis. Arthritis Res. Ther. 2017;19:166.
Not in our library10.1186/s13075-017-1375-0
133.
Expression and function of wingless and frizzled homologs in rheumatoid arthritis · 2000
Not checked
134.
Rauner M., Stein N., Winzer M., Goettsch C., Zwerina J., Schett G., Distler J.H., Albers J., Schulze J., Schinke T., et al. WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production. J. Bone Miner. Res. 2012;27:575-585.
Not in our library10.1002/jbmr.1488
135.
Rodriguez-Trillo A., Mosquera N., Pena C., Rivas-Tobío F., Mera-Varela A., Gonzalez A., Conde C. Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes. Front. Immunol. 2020;11:555245.
Not in our library10.3389/fimmu.2020.555245
136.
SFRP5 Enhances Wnt5a Induced-Inflammation in Rheumatoid Arthritis Fibroblast-Like Synoviocytes · 2021
Not checked
137.
Zhang F., Wei K., Slowikowski K., Fonseka C.Y., Rao D.A., Kelly S., Goodman S.M., Tabechian D., Hughes L.B., Salomon-Escoto K., et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 2019;20:928-942.
Not in our library10.1038/s41590-019-0378-1
138.
Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis · 2018
No notice
139.
Croft A.P., Campos J., Jansen K., Turner J.D., Marshall J., Attar M., Savary L., Wehmeyer C., Naylor A.J., Kemble S., et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019;570:246-251.
Not in our library10.1038/s41586-019-1263-7
140.
Wei K., Korsunsky I., Marshall J.L., Gao A., Watts G.F.M., Major T., Croft A.P., Watts J., Blazar P.E., Lange J.K., et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020;582:259-264.
Not in our library10.1038/s41586-020-2222-z
141.
Wei K., Nguyen H.N., Brenner M.B. Fibroblast pathology in inflammatory diseases. J. Clin. Investig. 2021;131:e149538.
Not in our library10.1172/jci149538
142.
Uehara S., Udagawa N., Mukai H., Ishihara A., Maeda K., Yamashita T., Murakami K., Nishita M., Nakamura T., Kato S., et al. Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a-Ror2 signaling. Sci. Signal. 2017;10:eaan0023.
Not in our library10.1126/scisignal.aan0023
143.
The Regulation of Bone Metabolism and Disorders by Wnt Signaling · 2019
No notice
144.
Yokota K., Sato K., Miyazaki T., Aizaki Y., Tanaka S., Sekikawa M., Kozu N., Kadono Y., Oda H., Mimura T. Characterization and Function of Tumor Necrosis Factor and Interleukin-6-Induced Osteoclasts in Rheumatoid Arthritis. Arthritis Rheumatol. 2021;73:1145-1154.
Not in our library10.1002/art.41666
145.
Rossini M., Viapiana O., Adami S., Fracassi E., Idolazzi L., Dartizio C., Povino M.R., Orsolini G., Gatti D. In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. Clin. Exp. Rheumatol. 2015;33:77-83.
Not in our library
146.
Murray E., Ellis A., Butylkova Y., Skup M., Kalabic J., Garg V. Systematic review and network meta-analysis: Effect of biologics on radiographic progression in rheumatoid arthritis. J. Comp. Eff. Res. 2018;7:959-974.
Not in our library10.2217/cer-2017-0106
147.
Segawa Y., Yamaura M., Aota S., Omata T., Tuzuike N., Itokazu Y., Oka H., Tamaki H., Nakamura T. Methotrexate maintains bone mass by preventing both a decrease in bone formation and an increase in bone resorption in adjuvant-induced arthritic rats. Bone. 1997;20:457-464.
Not in our library10.1016/s8756-3282(97)00023-9
148.
Kanagawa H., Masuyama R., Morita M., Sato Y., Niki Y., Kobayashi T., Katsuyama E., Fujie A., Hao W., Tando T., et al. Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors. J. Bone Miner. Metab. 2016;34:526-531.
Not in our library10.1007/s00774-015-0702-2
149.
Poutoglidou F., Pourzitaki C., Manthou M.E., Samoladas E., Saitis A., Malliou F., Kouvelas D. Infliximab prevents systemic bone loss and suppresses tendon inflammation in a collagen-induced arthritis rat model. Inflammopharmacology. 2021;29:661-672.
Not in our library10.1007/s10787-021-00815-w
150.
Kaste S.C., Jones-Wallace D., Rose S.R., Boyett J.M., Lustig R.H., Rivera G.K., Pui C.H., Hudson M.M. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: Frequency of occurrence and risk factors for their development. Leukemia. 2001;15:728-734.
Not in our library10.1038/sj.leu.2402078
151.
di Munno O., Mazzantini M., Sinigaglia L., Bianchi G., Minisola G., Muratore M., la Corte R., di Matteo L., Canesi B., Caminiti M., et al. Effect of low dose methotrexate on bone density in women with rheumatoid arthritis: Results from a multicenter cross-sectional study. J. Rheumatol. 2004;31:1305-1309.
Not in our library
152.
Vis M., Voskuyl A.E., Wolbink G.J., Dijkmans B.A., Lems W.F. Bone mineral density in patients with rheumatoid arthritis treated with infliximab. Ann. Rheum. Dis. 2005;64:336-337.
Not in our library10.1136/ard.2003.017780
153.
Vis M., Havaardsholm E.A., Haugeberg G., Uhlig T., Voskuyl A.E., van de Stadt R.J., Dijkmans B.A., Woolf A.D., Kvien T.K., Lems W.F. Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2006;65:1495-1499.
Not in our library10.1136/ard.2005.044198
154.
Marotte H., Pallot-Prades B., Grange L., Gaudin P., Alexandre C., Miossec P. A 1-year case-control study in patients with rheumatoid arthritis indicates prevention of loss of bone mineral density in both responders and nonresponders to infliximab. Arthritis Res. Ther. 2007;9:R61.
Not in our library10.1186/ar2219
155.
Chopin F., Garnero P., le Henanff A., Debiais F., Daragon A., Roux C., Sany J., Wendling D., Zarnitsky C., Ravaud P., et al. Long-term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2008;67:353-357.
Not in our library10.1136/ard.2007.076604
156.
Eekman D.A., Vis M., Bultink I.E., Kuik D.J., Voskuyl A.E., Dijkmans B.A., Lems W.F. Stable bone mineral density in lumbar spine and hip in contrast to bone loss in the hands during long-term treatment with infliximab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2011;70:389-390.
Not in our library10.1136/ard.2009.127787
157.
Wijbrandts C.A., Klaasen R., Dijkgraaf M.G., Gerlag D.M., van Eck-Smit B.L., Tak P.P. Bone mineral density in rheumatoid arthritis patients 1 year after adalimumab therapy: Arrest of bone loss. Ann. Rheum. Dis. 2009;68:373-376.
Not in our library10.1136/ard.2008.091611
158.
Krieckaert C.L., Nurmohamed M.T., Wolbink G., Lems W.F. Changes in bone mineral density during long-term treatment with adalimumab in patients with rheumatoid arthritis: A cohort study. Rheumatology. 2013;52:547-553.
Not in our library10.1093/rheumatology/kes320
159.
Gulyás K., Horváth Á., Végh E., Pusztai A., Szentpétery Á., Pethö Z., Váncsa A., Bodnár N., Csomor P., Hamar A., et al. Effects of 1-year anti-TNF-α therapies on bone mineral density and bone biomarkers in rheumatoid arthritis and ankylosing spondylitis. Clin. Rheumatol. 2020;39:167-175.
Not in our library10.1007/s10067-019-04771-3
160.
Orsolini G., Adami G., Adami S., Viapiana O., Idolazzi L., Gatti D., Rossini M. Short-Term Effects of TNF Inhibitors on Bone Turnover Markers and Bone Mineral Density in Rheumatoid Arthritis. Calcif. Tissue Int. 2016;98:580-585.
Not in our library10.1007/s00223-016-0114-x
161.
Abu-Shakra M., Zisman D., Balbir-Gurman A., Amital H., Levy Y., Langevitz P., Tishler M., Molad Y., Aamar S., Roser I., et al. Effect of Tocilizumab on Fatigue and Bone Mineral Density in Patients with Rheumatoid Arthritis. Isr. Med. Assoc. J. IMAJ. 2018;20:239-244.
Not in our library
162.
Kume K., Amano K., Yamada S., Kanazawa T., Ohta H., Hatta K., Amano K., Kuwaba N. The effect of tocilizumab on bone mineral density in patients with methotrexate-resistant active rheumatoid arthritis. Rheumatology. 2014;53:900-903.
Not in our library10.1093/rheumatology/ket468
163.
Briot K., Rouanet S., Schaeverbeke T., Etchepare F., Gaudin P., Perdriger A., Vray M., Steinberg G., Roux C. The effect of tocilizumab on bone mineral density, serum levels of Dickkopf-1 and bone remodeling markers in patients with rheumatoid arthritis. Jt. Int. Bone Spine. 2015;82:109-115.
Not in our library10.1016/j.jbspin.2014.10.015
164.
Boyapati A., Msihid J., Fiore S., van Adelsberg J., Graham N.M., Hamilton J.D. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: A biomarker study of MOBILITY. Arthritis Res. Ther. 2016;18:225.
Not in our library10.1186/s13075-016-1132-9
165.
Gabay C., Msihid J., Zilberstein M., Paccard C., Lin Y., Graham N.M.H., Boyapati A. Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: A biomarker substudy of the phase 3 TARGET study. RMD Open. 2018;4:e000607.
Not in our library10.1136/rmdopen-2017-000607
166.
Gabay C., Burmester G.R., Strand V., Msihid J., Zilberstein M., Kimura T., van Hoogstraten H., Boklage S.H., Sadeh J., Graham N.M.H., et al. Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes. Arthritis Res. Ther. 2020;22:70.
Not in our library10.1186/s13075-020-02163-6
167.
Tada M., Inui K., Sugioka Y., Mamoto K., Okano T., Koike T. Abatacept might increase bone mineral density at femoral neck for patients with rheumatoid arthritis in clinical practice: AIRTIGHT study. Rheumatol. Int. 2018;38:777-784.
Not in our library10.1007/s00296-017-3922-z
168.
Hamar A., Szekanecz Z., Pusztai A., Czókolyová M., Végh E., Pethő Z., Bodnár N., Gulyás K., Horváth Á., Soós B., et al. Effects of one-year tofacitinib therapy on bone metabolism in rheumatoid arthritis. Osteoporos. Int. 2021;32:1621-1629.
Not in our library10.1007/s00198-021-05871-0
169.
Thudium C.S., Bay-Jensen A.C., Cahya S., Dow E.R., Karsdal M.A., Koch A.E., Zhang W., Benschop R.J. The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis. Arthritis Res. Ther. 2020;22:235.
Not in our library10.1186/s13075-020-02340-7
170.
Mageed R.A., Adams G., Woodrow D., Podhajcer O.L., Chernajovsky Y. Prevention of collagen-induced arthritis by gene delivery of soluble p75 tumour necrosis factor receptor. Gene Ther. 1998;5:1584-1592.
Not in our library10.1038/sj.gt.3300785
171.
Saidenberg-Kermanac’h N., Corrado A., Lemeiter D., deVernejoul M.C., Boissier M.C., Cohen-Solal M.E. TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone. 2004;35:1200-1207.
Not in our library10.1016/j.bone.2004.07.004
172.
De Benedetti F., Rucci N., Del Fattore A., Peruzzi B., Paro R., Longo M., Vivarelli M., Muratori F., Berni S., Ballanti P., et al. Impaired skeletal development in interleukin-6-transgenic mice: A model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum. 2006;54:3551-3563.
Not in our library10.1002/art.22175
173.
Peruzzi B., Cappariello A., Del Fattore A., Rucci N., De Benedetti F., Teti A. c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. Nat. Commun. 2012;3:630.
Not in our library10.1038/ncomms1651
174.
Takeuchi T., Yoshida H., Tanaka S. Role of interleukin-6 in bone destruction and bone repair in rheumatoid arthritis. Autoimmun. Rev. 2021;20:102884.
Not in our library10.1016/j.autrev.2021.102884
175.
Liu H., Feng W., Yimin, Cui J., Lv S., Hasegawa T., Sun B., Li J., Oda K., Amizuka N., et al. Histological Evidence of Increased Osteoclast Cell Number and Asymmetric Bone Resorption Activity in the Tibiae of Interleukin-6-Deficient Mice. J. Histochem. Cytochem. Off. J. Histochem. Soc. 2014;62:556-564.
Not in our library10.1369/0022155414537830
176.
Yoshida H., Suzuki M., Tanaka K., Takeda S., Yogo K., Matsumoto Y. Anti-interleukin-6 receptor antibody prevents loss of bone structure and bone strength in collagen-induced arthritis mice. Scand. J. Rheumatol. 2018;47:384-391.
Not in our library10.1080/03009742.2017.1416667
177.
Finzel S., Kraus S., Figueiredo C.P., Regensburger A., Kocijan R., Rech J., Schett G. Comparison of the effects of tocilizumab monotherapy and adalimumab in combination with methotrexate on bone erosion repair in rheumatoid arthritis. Ann. Rheum. Dis. 2019;78:1186-1191.
Not in our library10.1136/annrheumdis-2018-214894
178.
Wang S.Y., Liu Y.Y., Ye H., Guo J.P., Li R., Liu X., Li Z.G. Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J. Rheumatol. 2011;38:821-827.
Not in our library10.3899/jrheum.100089
179.
Seror R., Boudaoud S., Pavy S., Nocturne G., Schaeverbeke T., Saraux A., Chanson P., Gottenberg J.E., Devauchelle-Pensec V., Tobón G.J., et al. Increased Dickkopf-1 in Recent-onset Rheumatoid Arthritis is a New Biomarker of Structural Severity. Data from the ESPOIR Cohort. Sci. Rep. 2016;6:18421.
Not in our library10.1038/srep18421
180.
Singh A., Gupta M.K., Mishra S.P. Study of correlation of level of expression of Wnt signaling pathway inhibitors sclerostin and dickkopf-1 with disease activity and severity in rheumatoid arthritis patients. Drug Discov. Ther. 2019;13:22-27.
Not in our library10.5582/ddt.2019.01011
181.
Cici D., Corrado A., Rotondo C., Cantatore F.P. Wnt Signaling and Biological Therapy in Rheumatoid Arthritis and Spondyloarthritis. Int. J. Mol. Sci. 2019;20:5552.
Not in our library10.3390/ijms20225552
182.
Roser-Page S., Vikulina T., Zayzafoon M., Weitzmann M.N. CTLA-4Ig-induced T cell anergy promotes Wnt-10b production and bone formation in a mouse model. Arthritis Rheumatol. 2014;66:990-999.
Not in our library10.1002/art.38319
183.
Roser-Page S., Vikulina T., Weiss D., Habib M.M., Beck G.R., Pacifici R., Lane T.F., Weitzmann M.N. CTLA-4Ig (abatacept) balances bone anabolic effects of T cells and Wnt-10b with antianabolic effects of osteoblastic sclerostin. Ann. N. Y. Acad. Sci. 2018;1415:21-33.
Not in our library10.1111/nyas.13643
184.
Axmann R., Herman S., Zaiss M., Franz S., Polzer K., Zwerina J., Herrmann M., Smolen J., Schett G. CTLA-4 directly inhibits osteoclast formation. Ann. Rheum. Dis. 2008;67:1603-1609.
Not in our library10.1136/ard.2007.080713
185.
Bozec A., Zaiss M.M., Kagwiria R., Voll R., Rauh M., Chen Z., Mueller-Schmucker S., Kroczek R.A., Heinzerling L., Moser M., et al. T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. Sci. Transl. Med. 2014;6:235ra260.
Not in our library10.1126/scitranslmed.3007764
186.
Okada H., Kajiya H., Omata Y., Matsumoto T., Sato Y., Kobayashi T., Nakamura S., Kaneko Y., Nakamura S., Koyama T., et al. CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages. J. Bone Miner. Res. 2019;34:1744-1752.
Not in our library10.1002/jbmr.3754
187.
Okada H., Okabe K., Tanaka S. Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption. Int. J. Mol. Sci. 2020;22:180.
Not in our library10.3390/ijms22010180
188.
Yamaoka K. Janus kinase inhibitors for rheumatoid arthritis. Curr. Opin. Chem. Biol. 2016;32:29-33.
Not in our library10.1016/j.cbpa.2016.03.006
189.
Sanpaolo E.R., Rotondo C., Cici D., Corrado A., Cantatore F.P. JAK/STAT pathway and molecular mechanism in bone remodeling. Mol. Biol. Rep. 2020;47:9087-9096.
Not in our library10.1007/s11033-020-05910-9
190.
Vidal B., Cascão R., Finnilä M.A.J., Lopes I.P., da Glória V.G., Saarakkala S., Zioupos P., Canhão H., Fonseca J.E. Effects of tofacitinib in early arthritis-induced bone loss in an adjuvant-induced arthritis rat model. Rheumatology. 2018;57:1461-1471.
Not in our library10.1093/rheumatology/kex258
191.
LaBranche T.P., Jesson M.I., Radi Z.A., Storer C.E., Guzova J.A., Bonar S.L., Thompson J.M., Happa F.A., Stewart Z.S., Zhan Y., et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 2012;64:3531-3542.
Not in our library10.1002/art.34649
192.
Gaber T., Brinkman A.C.K., Pienczikowski J., Diesing K., Damerau A., Pfeiffenberger M., Lang A., Ohrndorf S., Burmester G.R., Buttgereit F., et al. Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing. Int. J. Mol. Sci. 2020;21:865.
Not in our library10.3390/ijms21030865
193.
Adam S., Simon N., Steffen U., Andes F.T., Scholtysek C., Müller D.I.H., Weidner D., Andreev D., Kleyer A., Culemann S., et al. JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci. Transl. Med. 2020;12:eaay4447.
Not in our library10.1126/scitranslmed.aay4447
194.
Fridman J.S., Scherle P.A., Collins R., Burn T.C., Li Y., Li J., Covington M.B., Thomas B., Collier P., Favata M.F., et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: Preclinical characterization of INCB028050. J. Immunol. 2010;184:5298-5307.
Not in our library10.4049/jimmunol.0902819
195.
Murakami K., Kobayashi Y., Uehara S., Suzuki T., Koide M., Yamashita T., Nakamura M., Takahashi N., Kato H., Udagawa N., et al. A Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro. PLoS ONE. 2017;12:e0181126.
Not in our library10.1371/journal.pone.0181126
196.
Ito M., Yamazaki S., Yamagami K., Kuno M., Morita Y., Okuma K., Nakamura K., Chida N., Inami M., Inoue T., et al. A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant-induced arthritis model. J. Pharmacol. Sci. 2017;133:25-33.
Not in our library10.1016/j.jphs.2016.12.001
197.
Van Rompaey L., Galien R., van der Aar E.M., Clement-Lacroix P., Nelles L., Smets B., Lepescheux L., Christophe T., Conrath K., Vandeghinste N., et al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J. Immunol. 2013;191:3568-3577.
Not in our library10.4049/jimmunol.1201348
198.
Baricitinib inhibits structural joint damage progression in patients with rheumatoid arthritis—a comprehensive review · 2021
Not checked
199.
Tanaka Y., Okumura H., Kim S., Dorey J., Wojciechowski P., Chorąży J., Kato D., Schultz N.M. Comparative Efficacy and Safety of Peficitinib Versus Tofacitinib and Baricitinib for Treatment of Rheumatoid Arthritis: A Systematic Review and Network Meta-Analysis. Rheumatol. Ther. 2021;8:729-750.
Not in our library10.1007/s40744-021-00284-1
200.
Tanaka Y., Kavanaugh A., Wicklund J., McInnes I.B. Filgotinib, a novel JAK1-preferential inhibitor for the treatment of rheumatoid arthritis: An overview from clinical trials. Mod. Rheumatol. 2021;32:1-11.
Not in our library10.1080/14397595.2021.1902617
201.
Van Vollenhoven R., Takeuchi T., Pangan A.L., Friedman A., Mohamed M.F., Chen S., Rischmueller M., Blanco R., Xavier R.M., Strand V. Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-Naive Patients With Moderately-to-Severely Active Rheumatoid Arthritis (SELECT-EARLY): A Multicenter, Multi-Country, Randomized, Double-Blind, Active Comparator-Controlled Trial. Arthritis Rheumatol. 2020;72:1607-1620.
Not in our library10.1002/art.41384
202.
Lee J.W., Kobayashi Y., Nakamichi Y., Udagawa N., Takahashi N., Im N.K., Seo H.J., Jeon W.B., Yonezawa T., Cha B.Y., et al. Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and prevents bone loss in mice. Biochem. Pharm. 2010;80:352-361.
Not in our library10.1016/j.bcp.2010.04.014
203.
Shakibaei M., Buhrmann C., Mobasheri A. Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone-derived cells. J. Biol. Chem. 2011;286:11492-11505.
Not in our library10.1074/jbc.m110.198713
204.
Resveratrol Mediated Modulation of Sirt-1/Runx2 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells: Potential Role of Runx2 Deacetylation · 2012
No notice
205.
Yamashita T., Uehara S., Udagawa N., Li F., Kadota S., Esumi H., Kobayashi Y., Takahashi N. Arctigenin inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways. PLoS ONE. 2014;9:e85878.
Not in our library10.1371/journal.pone.0085878
206.
Kim S.Y., Schneeweiss S., Liu J., Solomon D.H. Effects of disease-modifying antirheumatic drugs on nonvertebral fracture risk in rheumatoid arthritis: A population-based cohort study. J. Bone Miner. Res. 2012;27:789-796.
Not in our library10.1002/jbmr.1489
207.
Kawai V.K., Grijalva C.G., Arbogast P.G., Curtis J.R., Solomon D.H., Delzell E., Chen L., Ouellet-Hellstrom R., Herrinton L., Liu L., et al. Initiation of tumor necrosis factor α antagonists and risk of fractures in patients with selected rheumatic and autoimmune diseases. Arthritis Care Res. 2013;65:1085-1094.
Not in our library10.1002/acr.21937
208.
Ozen G., Pedro S., Wolfe F., Michaud K. Medications associated with fracture risk in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2019;78:1041-1047.
Not in our library10.1136/annrheumdis-2019-215328

Cited by papers we hold 1

Systemic complications of rheumatoid arthritis: Focus on pathogenesis and treatment · 2022
No notice

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.