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Cytokine-Mediated Bone Destruction in Rheumatoid Arthritis

Seung Min Jung, Kyoung Woon Kim, Chul-Woo Yang and 2 more

Journal of Immunology Research · 2014 · Review

doi:10.1155/2014/263625

Abstract

Bone homeostasis, which involves formation and resorption, is an important process for maintaining adequate bone mass in humans. Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and bone loss, leading to joint destruction and deformity, and is a representative disease of disrupted bone homeostasis. The bone loss and joint destruction are mediated by immunological insults by proinflammatory cytokines and various immune cells. The connection between bone and immunity has been intensely studied and comprises the emerging field of osteoimmunology. Osteoimmunology is an interdisciplinary science investigating the interplay between the skeletal and the immune systems. The main contributors in osteoimmunology are the bone effector cells, such as osteoclasts or osteoblasts, and the immune cells, particularly lymphocytes and monocytes. Physiologically, osteoclasts originate from immune cells, and immune cells regulate osteoblasts and vice versa. Pathological conditions such as RA might affect these interactions, thereby altering bone homeostasis, resulting in the unfavorable outcome of bone destruction. In this review, we describe the osteoclastogenic roles of the proinflammatory cytokines and immune cells that are important in the pathophysiology of RA.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Rheumatoid arthritis (RA) is a devastating autoimmune disease characterized by progressive bone destruction. Under physiological conditions, bone remodeling occurs continually, as a coordinated process that results in the formation and degradation of bone. This process is a balance between bone formation, which is mediated by osteoblasts, and bone resorption, which is regulated by osteoclasts, and ensures bone homeostasis. In pathological conditions such as RA, bone homeostasis is disrupted, resulting in uncoordinated osteoclast formation.

Osteoclasts are generated from precursor cells that are usually of the monocyte-macrophage lineage. Interactions between receptor activator of the nuclear factor kappa B (RANK) and its ligand (RANKL) are essential in osteoclastogenesis. RANK on monocyte binds to RANKL, initiating osteoclast differentiation. Under physiological conditions, the main source of RANKL is osteoblasts. However, immune cells and fibroblast-like synoviocytes (FLS) are the main source of RANKL in pathological conditions such as arthritic RA joints (Figure 1). Several systemic and local factors influence the process of osteoclastogenesis. In RA, excessive activation of the immune system could affect the formation and function of osteoclasts. Proinflammatory cytokines tend to be osteoclastogenic; however, the opposite has also been observed. In our literature review, proinflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, IL-11, IL-17, and tumor necrosis factor (TNF)-α were frequently reported to be osteoclastogenic, and IL-4, IL-10, IL-13, IL-18, interferon (IFN)-γ, and IFN-β were anti-osteoclastogenic. T cell subpopulations have been studied for their contribution to osteoimmunology. T helper 17 cells (Th17 cells), a specific subtype of T helper cells that produce IL-17 and RANKL, were reported to be osteoclastogenic, whereas the classical Th1 and Th2 cells were generally reported to be anti-osteoclastogenic through their production of IFN-γ (Th1) and IL-4 (Th2).

We could not draw uniform conclusions about the various factors involved in osteoclastogenesis. Some proinflammatory cytokines, such as IL-7, IL-12, IL-23, and TGF-β, possess dual osteoclastogenic and anti-osteoclastogenic properties. Their net effect depends on the specific pathophysiological conditions in in vivo models, whereas it depends on the developmental stage of the osteoclasts in in vitro experiments. The determination of their exact role in the bone microenvironment is even more difficult because these cytokines can have synergistic or antagonistic effects on osteoclasts.

The joint structure is invaded and the bone is destroyed by the pannus, which contains a massive infiltration of immune cells, proliferative vessels, and increased numbers of osteoclasts (Figures 2(a) and 2(b)). These complicated structures are frequently observed in RA at the synovium-bone interface (Figure 2(c)). This review will address immune-mediated bone destruction in two sections. First, the osteoclastogenic role of proinflammatory cytokines will be discussed. In the following section, the osteoclastogenic role of inflammatory cells that play important roles in the pathogenesis of RA will be described.

2. Cytokines and Bone: The Osteoclastogenic Effect of Proinflammatory Cytokines

Proinflammatory cytokines promote osteoclastogenesis via RANKL expression. Some researchers have shown that proinflammatory cytokines such as TNF-α, IL-1, and IL-6 are capable of inducing osteoclast differentiation independently of RANKL. Others showed that a minimal level of RANKL is essential for TNF-α-induced osteoclastogenesis, revealing that TNF-α alone does not induce osteoclast formation. To clarify this controversy, we adopted a simplified monocellular culture system instead of a co-culture system, which consists of osteoblasts and bone marrow cells. In our experience, permissive levels of RANKL were required for cytokine-associated osteoclastogenesis. IL-1 increased and IL-6 decreased the number of mature osteoclasts in a dose-dependent manner. Treatment with IL-23, IL-17, or TNF-α resulted in various responses according to the exposure time and the cytokine concentration.

The effects of important cytokines on osteoclastogenesis in vitro and in vivo are summarized in Table 1. Based on laboratory observations, cytokine-targeting therapies were tested in bone resorptive conditions. The results of experimental and clinical trials are presented in Table 2.

2.1. TNF-α

TNF-α has received attention from immunologists and rheumatologists because several TNF-α inhibitors show enormous pharmaceutical success in treating RA. TNF-α is produced by activated T cells and is involved in inflammation- and cancer-induced bone loss. Treatment with TNF-α inhibitors results in decreased inflammation and bone protection in RA patients. In vivo blockade of TNF-α reduces bone resorption in postmenopausal osteoporosis. Thus, TNF-α is regarded as a major contributor to bone destruction and osteoclast formation.

TNF-α promotes bone destruction by upregulating the production of RANKL and macrophage colony-stimulating factor (M-CSF) from osteoblasts and stromal cells, and by augmenting differentiation into osteoclasts independently of RANK-RANKL signaling. In addition, TNF-α and RANKL synergistically upregulate the expression of RANK. This osteoclastogenic effect of TNF-α is closely associated with other inflammatory cytokines, including IL-1 and M-CSF. Although osteoclastogenesis is a more dominant mechanism in the bone erosion of inflammatory disease, osteoblast formation is also affected by TNF-α. TNF-α inhibits osteoblast differentiation primarily through TNF-receptor 1 signaling.

2.2. IL-1

IL-1, a proinflammatory cytokine, is highly expressed in patients with RA. An earlier study showed a prominent protective effect of IL-1 blockade against structural damage in an arthritis animal model, suggesting a crucial effect of IL-1 on bone metabolism. Animal models with a deficiency of IL-1 signaling present with reduced osteoclastogenesis, leading to significantly increased levels of bone density, trabecular bone mass, and cortical thickness. IL-1 also plays an important role in the bone loss induced by estrogen deficiency; the level of IL-1 increases after menopause and decreases with estrogen replacement. Bone resorption is suppressed by blockade of IL-1 in postmenopausal women.

IL-1 induces RANKL to promote osteoclastogenesis through the production of prostaglandin E in periodontal tissue. Furthermore, IL-1 might exert a bone resorptive effect via an alternative pathway independent of the RANK/RANKL signal. IL-1 is essential for TNF-α-induced osteoclastogenesis. Human TNF-α transgenic mice lacking IL-1β were protected from systemic bone loss regardless of sustained inflammation. The activation of p38 mitogen-activated proteinase kinase is involved in TNF-α- and IL-1-mediated osteoclastogenesis by upregulating RANKL expression in stromal cells and stimulating osteoclast precursor differentiation.

2.3. IL-6

Dysregulation of IL-6 is frequently observed in RA patients. IL-6 is responsible for synovial inflammation as well as the structural damage of RA. An IL-6 receptor antagonist, a new immunotherapeutic, reduced bone turnover, favoring bone protection in RA patients. IL-6 is also involved in other diseases associated with accelerated bone turnover, such as multiple myeloma and Paget's disease of bone.

The previous data indicate the dual functions of IL-6 on bone remodeling. The addition of IL-6 and the soluble IL-6 receptor into bone tissue cultures stimulates bone resorption through increased RANKL expression on osteoblasts via activation of the STAT3 pathway. However, IL-6 exhibits a direct inhibitory effect on RANK signaling in osteoclast progenitor cells in the absence of other supporting cells.

In vivo studies also suggest that the role of IL-6 varies in a context-dependent manner. IL-6 transgenic mice with a high level of circulating IL-6 exhibited enhanced osteoclastogenesis, leading to impaired skeletal growth at the prepubertal stage but decreased osteoclast formation at the adult stage. Under physiological conditions, IL-6 deficiency resulted in no detectable change in osteoclast number. However, IL-6 knockout mice were protected against ovariectomy-induced bone loss. IL-6 knockout mice with experimental arthritis showed significantly decreased osteoclastogenic activity and impaired osteoclast recruitment to inflammatory sites. These results indicate that IL-6 is associated with bone loss from inflammation and estrogen deprivation. IL-6, along with TGF-β, induces the differentiation of naïve T cells into Th17 cells, which are typically osteoclastogenic.

2.4. IL-17

IL-17 is predominantly expressed by Th17 cells, a specific type of human T helper cells. It is hypothesized that this cytokine plays a crucial role in inflammation and the development of autoimmune diseases, including RA. There is evidence that IL-17 enhances osteoclastogenesis by a RANKL-RANK dependent mechanism. Studies of an arthritis animal model indicate that IL-17 induces the expression of RANKL and proinflammatory cytokines such as IL-1 and TNF-α. These inflammatory mediators (IL-17, IL-1, TNF-α, and RANKL) interact with each other in the progression of RA. IL-17A also upregulates the expression of RANK on osteoclast precursors and increases their sensitivity to RANKL. Similarly, treatment with an IL-17 neutralizing antibody inhibited bone destruction in collagen-induced arthritis. However, the mechanisms of action of IL-17 in bone erosion remain to be determined, particularly in association with other osteoclastogenic cytokines such as IL-1, TNF-α, and RANKL.

2.5. IL-23

One of the most important stimuli for IL-17 synthesis is IL-23 produced by activated dendritic cells and macrophages. IL-23 is implicated in inflammatory diseases, in association with IL-17. Accordingly, the IL-23/IL-17 axis plays a critical role in controlling inflammatory bone loss. Recent work suggests that osteoclastogenesis is promoted by IL-23 and inhibited by an anti-IL-23 antibody. By contrast, another study shows the indirect inhibition of osteoclast differentiation by IL-23 in vitro. Under physiological conditions, IL-23 promotes higher bone mass in long bones by limiting bone resorption near the growth plate in vivo. These conflicting data suggest different roles for this cytokine in physiological or inflammatory bone turnover.

3. Immune Cells and Bone: The Osteoclastogenic Effect of Inflammatory Cells

Various immune cells play important roles in the pathogenesis of RA. These cells comprise the rheumatoid synovium that is continuously inflamed and invades adjacent tissue, resulting in joint destruction (Figure 2). Although osteoclasts are the final effectors of bone erosion, osteoclastogenesis is regulated by various cells in the RA synovium. FLS are the main cellular component of the matrix that is involved in bone turnover. Monocytes, T cells, B cells, and neutrophils also infiltrate the RA synovium and interact with each other. These cells vigorously contribute to osteoclast formation under inflammatory conditions by producing osteoclastogenic cytokines or RANKL (Figure 3).

3.1. Fibroblast-Like Synoviocytes (FLS)

Under physiological conditions, the synovium secretes synovial fluid and provides mechanical stability to the joint. However, pathological conditions such as RA render the synovium more aggressive. The synovium forms a pannus with inflammatory cells, enabling invasion into the bone. Histopathology demonstrates increased bone resorption at the bone-pannus interface in the joints of patients with RA. Thus, FLS play an active role in the pathogenesis of RA.

The bone and cartilage destruction in RA patients is partly mediated by metalloproteinases secreted by activated synoviocytes and chondrocytes. More importantly, bone destruction is further exacerbated by osteoclasts induced by the RA synovium. We reported that RANKL is produced by FLS from RA patients (RA-FLS) and that osteoclasts are formed in cocultures of RA-FLS and human monocytes. Consistent with a previous report, this result indicates that RA-FLS have the capability to support osteoclast differentiation. In RA, FLS upregulate the expression of RANKL and osteoclastogenic cytokines. Earlier studies show that RANKL in RA-FLS can be increased by IL-23, IL-22, and SDF-1. Furthermore, FLS produce osteoclastogenic cytokines such as IL-6 in response to IL-17 and IL-23. These inflammatory mediators from stimulated RA-FLS act on stromal cells to upregulate RANKL expression and on osteoclast precursor cells to promote differentiation into osteoclasts (Figure 4).

3.2. Monocyte and Dendritic Cells

Bloodstream monocytes migrate into inflammatory tissue where they differentiate into resident macrophages and dendritic cells (DCs). Macrophages and DCs express a variety of inflammatory cytokines involved in the pathogenesis of RA.

Synovial macrophages play a central role in rheumatoid inflammation. TNF-α, IL-1, and IL-6 are largely produced by activated macrophages and synovial fibroblasts in the RA synovium. As discussed above, these cytokines directly exert osteoclastogenic effects, either synergistically with RANKL or independently of the RANKL signaling pathway. Moreover, macrophages in the RA synovium also secrete TGF-β, IL-21, and IL-23 to differentiate CD4+ T cells into Th17 cells, which are typically referred to as osteoclastogenic T cells.

DC, highly differentiated antigen-presenting cells, interact with T cells and B cells in RA. The physiological function of DC in bone remodeling appears to be modest, as DCs are not frequently observed in bone or the adjacent stroma under normal conditions. By contrast, active lesions of RA and periodontitis retain mature and immature DCs. At these sites, DCs contact and interact with T cells to elicit inflammatory processes that involve RANK-RANKL signaling. In multiple myeloma, DCs promote osteoclastogenesis, leading to bone destruction, possibly by activation of RANK-RANKL signaling and the overproduction of IL-17.

DCs can also affect bone metabolism in a more direct manner. Rivollier and colleagues showed that human monocyte-derived DCs transdifferentiate into osteoclasts in the presence of M-CSF and RANKL in vitro, suggesting that DCs might directly contribute to osteoclastogenesis. Alnaeeli et al. tested whether the interaction between DCs and T cells supports osteoclast development using an in vitro co-culture system of bone marrow-derived CD11c+ DC and CD4+ T cells. Murine CD11c+ DC developed into functional osteoclasts after interactions with CD4+ T cells and stimulation with microbial or protein antigens. Adoptive transfer of DC-derived osteoclasts could induce bone resorption in NOD/SCID mice calvarias in vivo. The differentiation of DCs into osteoclasts is frequently reported in the pathogenesis of multiple myeloma.

3.3. T Cells

T cells are one of the key regulators of synovial inflammation in RA, having both stimulatory and inhibitory roles. T cells can also play a destructive or a protective role in bone metabolism in a context- and subtype-dependent manner.

In the resting state, T cells seem to have a positive effect on bone mineral density, as T cell depletion increased osteoclastogenesis in vitro and accelerated bone resorption in vivo. T cell-deficient nude mice have significantly higher numbers of osteoclasts and reduced bone density compared to controls.

In response to antigenic stimuli, CD4+ T cells differentiate into distinct effector subsets, Th1 and Th2 cells, which are classically defined on the basis of cytokine production profiles. Th1 cells are characterized by the secretion of IFN-γ, IL-2, IL-12, TNF-α, and TNF-β, and are involved in the elimination of intracellular pathogens. Th2 cells produce IL-4, IL-5, IL-6, IL-9, and IL-13, and are responsible for parasite eradication and allergic disorders. In one comprehensive study, Th1 and Th2 cells were shown to inhibit osteoclastogenesis through IFN-γ and IL-4, respectively. However, the bone-preserving effects of Th1 and Th2 cells are not certain, because contradictory responses have been observed in inflammatory conditions. Infection and inflammation could activate T cells to produce osteoclastogenic cytokines such as TNF-α and RANKL. In the pathogenic state, lymphocytes express significantly higher levels of RANKL and have the capacity to induce RANKL-dependent osteoclast differentiation, unlike in healthy conditions. In addition, IFN-γ exerts a bone resorptive effect instead of a bone-protective effect in an animal model with ovariectomy, infection, and inflammation. Thus, further research is required to understand the net effect of Th1/Th2 cells in disease states such as RA.

Th17 cells, a more recently characterized subset of CD4+ T cells, have been shown to be more osteoclastogenic. Th17 cells are produced when naïve T cells are activated by TGF-β and IL-6 in mice or TGF-β and inflammatory cytokines in humans. Th17 cell play a pivotal role in the pathogenesis of RA through the production of Th17 signature cytokines. Since IL-17 is predominantly produced by Th17 cells and is closely associated with osteoclastogenesis, Th17 cells are likely to affect bone metabolism primarily through IL-17. IL-17 directly induces the expression of RANKL from surrounding cells and facilitates the recruitment of inflammatory cells, leading to an abundance of inflammatory cytokines such as TNF-α and IL-1. Moreover, Th17 cells drive RA-FLS to produce IL-6, IL-8, and matrix metalloproteinases, which potentiate structural damage. A prominent role for Th17 cells has been demonstrated in bone destructive diseases such as RA and multiple myeloma (Figure 5).

3.4. B Cells

Multiple myeloma is a malignant B cell disease characterized by multiple bone lesions. These are caused by plasma cells expressing RANKL, which stimulate osteoclast formation, leading to osteolysis. This phenomenon indicates that B cells could affect bone metabolism via RANKL expression. In RA, the pathophysiologic role of B cells is highlighted by the therapeutic success of B cell-depleting therapy with an anti-CD20 monoclonal antibody (rituximab). B cells play an important role in producing autoantibodies. Although the role of autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibody is not fully understood, these autoantibodies are associated with more severe bone destruction. Treatment with rituximab reduced bone destruction as well as joint inflammation. Taken together, these findings indicate that B cells contribute to bone destruction through RANKL expression and the production of autoantibodies in cooperation with other immune cells.

3.5. Neutrophils

The neutrophil is the most abundant type of white blood cell in mammals, and comprises an essential part of the innate immune system. Neutrophils normally circulate in the bloodstream and migrate to the site of inflammation in response to inflammatory stimuli. In the RA synovium, neutrophils regulate inflammation through the secretion of inflammatory mediators. Histological analysis of bony lesions in humans and animal models indicates the involvement of neutrophils in pathogenic bone remodeling. Infiltration of neutrophils is observed in human periodontitis and experimental arthritis. The RANKL-RANK-osteoprotegerin pathway is upregulated in activated neutrophils from inflammatory sites. Membrane RANKL on neutrophils is strongly overexpressed after stimulation with lipopolysaccharide and thus mediates osteoclastic bone resorption through the interactions between neutrophils and osteoclasts. The osteoclastogenic effect of neutrophils could be reproduced with purified neutrophil membranes, but not with culture supernatants from activated neutrophils. Thus, the effect of RANKL in activated neutrophils is predominantly mediated by the membrane-bound form, in contrast to activated T cells, where RANKL signaling is mediated by both cell surface and soluble RANKL. In addition, neutrophils affect the function of osteoblasts in children on chronic glucocorticoid therapy and in patients with tophaceous gout, resulting in altered bone remodeling.

4. Conclusions

The human body attempts to maintain bone mass in order to maintain skeletal strength. Bone mass is not static but dynamic, and results from the formation or resorbtion of the bony matrix by osteoblasts or osteoclasts. In pathological states such as RA, in which bone resorption is favored over bone formation, osteoblasts are outnumbered by osteoclasts. Osteoclastogenesis is also favored over osteoblastogenesis by the inflammatory milieu. Recent studies have shown that numerous cytokines and immune cells have osteoclastogenic effects, although their exact roles in pathological states are difficult to determine because of the complexity of immune networks in the human body. Proinflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-17 tend to be osteoclastogenic. The immune cells that participate in the pathogenesis of RA often enhance osteoclastogenesis by upregulating RANKL directly or by secreting proinflammatory cytokines that influence RANKL expression indirectly. Understanding the precise mechanisms of immune-mediated bone destruction would increase opportunities for target-specific inhibition of bone erosion or osteoporosis. Therapeutic interventions specifically targeting osteoclastogenesis might enable clinicians to spare bone mass in RA patients.

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    Garnero P, Thompson E, Woodworth T, Smolen JS. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis and Rheumatism. 2010;62(1):33-43.

    Not in our library10.1002/art.25053

  42. 42.

    Karsdal MA, Schett G, Emery P, et al. IL-6 receptor inhibition positively modulates bone balance in rheumatoid arthritis patients with an inadequate response to anti-tumor necrosis factor therapy: biochemical marker analysis of bone metabolism in the tocilizumab RADIATE study (NCT00106522). Seminars in Arthritis and Rheumatism. 2012;42(2):131-139.

    Not in our library10.1016/j.semarthrit.2012.01.004

  43. 43.

    Ehrlich LA, Roodman GD. The role of immune cells and inflammatory cytokines in Paget's disease and multiple myeloma. Immunological Reviews. 2005;208:252-266.

    Not in our library10.1111/j.0105-2896.2005.00323.x

  44. 44.

    Palmqvist P, Persson E, Conaway HH, Lerner UH. IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-κB ligand, osteoprotegerin, and receptor activator of NF-κB in mouse calvariae. The Journal of Immunology. 2002;169(6):3353-3362.

    Not in our library10.4049/jimmunol.169.6.3353

  45. 45.

    O'Brien CA, Lin SC, Bellido T, Manolagas SC. Expression levels of gp130 in bon e marrow stromal cells determine the magnitude of osteoclastogenic signals generated by IL-6-type cytokines. Journal of Cellular Biochemistry. 2000;79(4):532-541.

    Not in our library10.1002/1097-4644(20001215)79:4<532::aid-jcb20>3.0.co;2-u

  46. 46.

    de Benedetti F, Rucci N, Del Fattore A, et al. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis and Rheumatism. 2006;54(11):3551-3563.

    Not in our library10.1002/art.22175

  47. 47.

    Kitamura H, Kawata H, Takahashi F, Higuchi Y, Furuichi T, Ohkawa H. Bone marrow neutrophilia and suppressed bone turnover in human interleukin-6 transgenic mice: a cellular relationship among hematopoietic cells, osteoblasts, and osteoclasts mediated by stromal cells in bone marrow. The American Journal of Pathology. 1995;147(6):1682-1692.

    Not in our library

  48. 48.

    Poli V, Balena R, Fattori E, et al. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO Journal. 1994;13(5):1189-1196.

    Not in our library10.1002/j.1460-2075.1994.tb06368.x

  49. 49.

    Wong PKK, Quinn JMW, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis and Rheumatism. 2006;54(1):158-168.

    Not in our library10.1002/art.21537

  50. 50.

    Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. New England Journal of Medicine. 2009;361(9):848-898.

    Not in our library10.1056/nejmra0707449

  51. 51.

    Yao Z, Painter SL, Fanslow WC, et al. Human IL-17: a novel cytokine derived from T cells. Journal of Immunology. 1995;155(12):5483-5486.

    Not in our library

  52. 52.

    Lubberts E, Koenders M, van den Berg WB. The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Research and Therapy. 2005;7(1):29-37.

    Not in our library10.1186/ar1478

  53. 53.
    Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors · 2010
    No notice
  54. 54.

    Chao CC, Chen SJ, Adamopoulos IE, et al. Anti-IL-17A therapy protects against bone erosion in experimental models of rheumatoid arthritis. Autoimmunity. 2011;44(3):243-252.

    Not in our library10.3109/08916934.2010.517815

  55. 55.

    Lubberts E, Koenders MI, Oppers-Walgreen B, et al. 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 and Rheumatism. 2004;50(2):650-659.

    Not in our library10.1002/art.20001

  56. 56.
    IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats · 2007
    No notice
  57. 57.

    Quinn JMW, Sims NA, Saleh H, et al. IL-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice. Journal of Immunology. 2008;181(8):5720-5729.

    Not in our library10.4049/jimmunol.181.8.5720

  58. 58.

    Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nature Reviews Rheumatology. 2013;9(1):24-33.

    Not in our library10.1038/nrrheum.2012.190

  59. 59.

    Tolboom TC, Pieterman E, van der Laan WH, et al. Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10. Annals of the Rheumatic Diseases. 2002;61(11):975-980.

    Not in our library10.1136/ard.61.11.975

  60. 60.

    Pap T, Meinecke I, Müller-Ladner U, Gay S. Are fibroblasts involved in joint destruction? Annals of the Rheumatic Diseases. 2005;64(4):iv52-iv54.

    Not in our library10.1136/ard.2005.042424

  61. 61.

    Takayanagi H, Oda H, Yamamoto S, et al. A new mechanism of bone destruction in rheumatoid arthritis: synovial fibroblasts induce osteoclastogenesis. Biochemical and Biophysical Research Communications. 1997;240(2):279-286.

    Not in our library10.1006/bbrc.1997.7404

  62. 62.

    Gravallese EM, Harada Y, Wang J, Gorn AH, Thornhill TS, Goldring SR. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. The American Journal of Pathology. 1998;152(4):943-951.

    Not in our library

  63. 63.

    Harris ED. Rheumatoid arthritis. Pathophysiology and implications for therapy. The New England Journal of Medicine. 1990;322(18):1277-1289.

    Not in our library10.1056/nejm199005033221805

  64. 64.

    Kim KW, Cho ML, Lee SH, et al. Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation. Immunology Letters. 2007;110(1):54-64.

    Not in our library10.1016/j.imlet.2007.03.004

  65. 65.

    Li X, Kim K, Cho M, et al. IL-23 induces receptor activator of NF-κB ligand expression in fibroblast-like synoviocytes via STAT3 and NF-κB signal pathways. Immunology Letters. 2010;127(2):100-107.

    Not in our library10.1016/j.imlet.2009.10.012

  66. 66.

    Kim KW, Kim HR, Park JY, et al. Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts. Arthritis and Rheumatism. 2012;64(4):1015-1023.

    Not in our library10.1002/art.33446

  67. 67.

    Kim HR, Kim KW, Kim BM, Jung HG, Cho ML, Lee SH. Reciprocal activation of CD4+ T cells and synovial fibroblasts by stromal cell-derived factor 1 promotes RANKL expression and osteoclastogenesis in rheumatoid arthritis. Arthritis and Rheumatism. 2014;66(3):538-548.

    Not in our library10.1002/art.38286

  68. 68.

    Liu FL, Chen CH, Chu SJ, et al. Interleukin (IL)-23 p19 expression induced by IL-1β in human fibroblast-like synoviocytes with rheumatoid arthritis via active nuclear factor-κB and AP-1 dependent pathway. Rheumatology. 2007;46(8):1266-1273.

    Not in our library10.1093/rheumatology/kem055

  69. 69.

    Hwang SY, Kim JY, Kim KW, et al. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-κB- and PI3-kinase/Akt-dependent pathways. Arthritis Research & Therapy. 2004;6(2):R120-128.

    Not in our library10.1186/ar1038

  70. 70.

    Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nature Reviews Immunology. 2011;11(11):762-774.

    Not in our library10.1038/nri3070

  71. 71.

    McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. The New England Journal of Medicine. 2011;365(23):2205-2219.

    Not in our library10.1056/nejmra1004965

  72. 72.

    Li J, Hsu H, Mountz JD. Managing macrophages in rheumatoid arthritis by reform or removal. Current Rheumatology Reports. 2012;14(5):445-454.

    Not in our library10.1007/s11926-012-0272-4

  73. 73.

    Cirrincione C, Pimpinelli N, Orlando L, Romagnoli P. Lamina propria dendritic cells express activation markers and contact lymphocytes in chronic periodontitis. Journal of Periodontology. 2002;73(1):45-52.

    Not in our library10.1902/jop.2002.73.1.45

  74. 74.

    Highton J, Kean A, Hessian PA, Thomson J, Rietveld J, Hart DNJ. Cells expressing dendritic cell markers are present in the rheumatoid nodule. The Journal of Rheumatology. 2000;27(2):339-346.

    Not in our library

  75. 75.

    Thomas R, MacDonald KPA, Pettit AR, Cavanagh LL, Padmanabha J, Zehntner S. Dendritic cells and the pathogenesis of rheumatoid arthritis. Journal of Leukocyte Biology. 1999;66(2):286-292.

    Not in our library10.1002/jlb.66.2.286

  76. 76.

    Page G, Lebecque S, Miossec P. Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: correlation with selective chemokine expression in rheumatoid synovium. Journal of Immunology. 2002;168(10):5333-5341.

    Not in our library10.4049/jimmunol.168.10.5333

  77. 77.

    Page G, Miossec P. RANK and RANKL expression as markers of dendritic cell-T cell interactions in paired samples of rheumatoid synovium and lymph nodes. Arthritis and Rheumatism. 2005;52(8):2307-2312.

    Not in our library10.1002/art.21211

  78. 78.

    Cutler CW, Jotwani R. Dendritic cells at the oral mucosal interface. Journal of Dental Research. 2006;85(8):678-689.

    Not in our library10.1177/154405910608500801

  79. 79.

    Tucci M, Stucci S, Strippoli S, Dammacco F, Silvestris F. Dendritic cells and malignant plasma cells: an alliance in multiple myeloma tumor progression? Oncologist. 2011;16(7):1040-1048.

    Not in our library10.1634/theoncologist.2010-0327

  80. 80.

    Dhodapkar KM, Barbuto S, Matthews P, et al. Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma. Blood. 2008;112(7):2878-2885.

    Not in our library10.1182/blood-2008-03-143222

  81. 81.

    Rivollier A, Mazzorana M, Tebib J, et al. Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment. Blood. 2004;104(13):4029-4037.

    Not in our library10.1182/blood-2004-01-0041

  82. 82.

    Alnaeeli M, Penninger JM, Teng YA. Immune interactions with CD4+ T cells promote the development of functional osteoclasts from murine CD11c+ dendritic cells. Journal of Immunology. 2006;177(5):3314-3326.

    Not in our library10.4049/jimmunol.177.5.3314

  83. 83.

    Kukreja A, Radfar S, Sun B, Insogna K, Dhodapkar MV. Dominant role of CD47-thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease. Blood. 2009;114(16):3413-3421.

    Not in our library10.1182/blood-2009-03-211920

  84. 84.

    John V, Hock JM, Short LL, Glasebrook AL, Galvin RJS. A role for CD8+ T lymphocytes in osteoclast differentiation in vitro. Endocrinology. 1996;137(6):2457-2463.

    Not in our library10.1210/endo.137.6.8641199

  85. 85.

    Li Y, Toraldo G, Li A, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109(9):3839-3848.

    Not in our library10.1182/blood-2006-07-037994

  86. 86.

    Mosmann TR, Cherwinski H, Bond MW. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology. 1986;136(7):2348-2357.

    Not in our library

  87. 87.

    Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383(6603):787-793.

    Not in our library10.1038/383787a0

  88. 88.

    Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology. 1989;7:145-173.

    Not in our library10.1146/annurev.iy.07.040189.001045

  89. 89.

    Sato K, Suematsu A, Okamoto K, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. Journal of Experimental Medicine. 2006;203(12):2673-2682.

    Not in our library10.1084/jem.20061775

  90. 90.

    Kawai T, Matsuyama T, Hosokawa Y, et al. B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease. The American Journal of Pathology. 2006;169(3):987-998.

    Not in our library10.2353/ajpath.2006.060180

  91. 91.

    Kotake S, Nanke Y, Mogi M, et al. IFN-γ-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL. European Journal of Immunology. 2005;35(11):3353-3363.

    Not in our library10.1002/eji.200526141

  92. 92.

    Volpe E, Servant N, Zollinger R, et al. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nature Immunology. 2008;9(6):650-657.

    Not in our library10.1038/ni.1613

  93. 93.

    van Hamburg JP, Asmawidjaja PS, Davelaar N, et al. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis and Rheumatism. 2011;63(1):73-83.

    Not in our library10.1002/art.30093

  94. 94.

    Noonan K, Marchionni L, Anderson J, Pardoll D, Roodman GD, Borrello I. A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood. 2010;116(18):3554-3563.

    Not in our library10.1182/blood-2010-05-283895

  95. 95.

    Maddur MS, Miossec P, Kaveri SV, Bayry J. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. The American Journal of Pathology. 2012;181(1):8-18.

    Not in our library10.1016/j.ajpath.2012.03.044

  96. 96.

    Matsumoto T, Abe M. Bone destruction in multiple myeloma. Annals of the New York Academy of Sciences. 2006;1068(1):319-326.

    Not in our library10.1196/annals.1346.035

  97. 97.

    Edwards JCW, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology. 2001;40(2):205-211.

    Not in our library10.1093/rheumatology/40.2.205

  98. 98.

    Edwards JCW, Szczepański L, Szechiński J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. The New England Journal of Medicine. 2004;350(25):2572-2581.

    Not in our library10.1056/nejmoa032534

  99. 99.

    Nakken B, Munthe LA, Konttinen YT, et al. B-cells and their targeting in rheumatoid arthritis—current concepts and future perspectives. Autoimmunity Reviews. 2011;11(1):28-34.

    Not in our library10.1016/j.autrev.2011.06.010

  100. 100.

    Cascão R, Rosário HS, Souto-Carneiro MM, Fonseca JE. Neutrophils in rheumatoid arthritis: more than simple final effectors. Autoimmunity Reviews. 2010;9(8):531-535.

    Not in our library10.1016/j.autrev.2009.12.013

  101. 101.

    Kantarci A, Oyaizu K, van Dyke TE. Neutrophil-mediated tissue injury in periodontal disease pathogenesis: findings from localized aggressive periodontitis. Journal of Periodontology. 2003;74(1):66-75.

    Not in our library10.1902/jop.2003.74.1.66

  102. 102.

    Hasturk H, Kantarci A, Ohira T, et al. RvE1 protects from local inflammation and osteoclast-mediated bone destruction in periodontitis. The FASEB Journal. 2006;20(2):401-403.

    Not in our library10.1096/fj.05-4724fje

  103. 103.

    Wipke BT, Allen PM. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. Journal of Immunology. 2001;167(3):1601-1608.

    Not in our library10.4049/jimmunol.167.3.1601

  104. 104.

    Poubelle PE, Chakravarti A, Fernandes MJ, Doiron K, Marceau A. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Research and Therapy. 2007;9(2, article R25).

    Not in our library10.1186/ar2137

  105. 105.

    Chakravarti A, Raquil M, Tessier P, Poubelle PE. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood. 2009;114(8):1633-1644.

    Not in our library10.1182/blood-2008-09-178301

  106. 106.

    Walsh NC, Alexander KA, Manning CA, et al. Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL. Genes and Immunity. 2013;14(5):336-345.

    Not in our library10.1038/gene.2013.29

  107. 107.

    Kanamaru F, Iwai H, Ikeda T, Nakajima A, Ishikawa I, Azuma M. Expression of membrane-bound and soluble receptor activator of NF-κB ligand (RANKL) in human T cells. Immunology Letters. 2004;94(3):239-246.

    Not in our library10.1016/j.imlet.2004.05.010

  108. 108.

    Brunetti G, Faienza MF, Piacente L, et al. High dickkopf-1 levels in sera and leukocytes from children with 21-hydroxylase deficiency on chronic glucocorticoid treatment. The American Journal of Physiology: Endocrinology and Metabolism. 2013;304(5):E546-E554.

    Not in our library10.1152/ajpendo.00535.2012

  109. 109.

    Allaeys I, Rusu D, Picard S, Pouliot M, Borgeat P, Poubelle PE. Osteoblast retraction induced by adherent neutrophils promotes osteoclast bone resorption: implication for altered bone remodeling in chronic gout. Laboratory Investigation. 2011;91(6):905-920.

    Not in our library10.1038/labinvest.2011.46

  110. 110.

    Boyce BF, Schwarz EM, Xing L. Osteoclast precursors: Cytokine-stimulated immunomodulators of inflammatory bone disease. Current Opinion in Rheumatology. 2006;18(4):427-432.

    Not in our library10.1097/01.bor.0000231913.32364.32

  111. 111.

    Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ. TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology. 2002;143(3):1108-1118.

    Not in our library10.1210/endo.143.3.8701

  112. 112.

    Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA. M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death and Differentiation. 2003;10(10):1165-1177.

    Not in our library10.1038/sj.cdd.4401285

  113. 113.

    Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. Tumor necrosis factor-α induces differentiation of and bone resorption by osteoclasts. Journal of Biological Chemistry. 2000;275(7):4858-4864.

    Not in our library10.1074/jbc.275.7.4858

  114. 114.

    Yarilina A, Xu K, Chen J, Ivashkiv LB. TNF activates calcium-nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(4):1573-1578.

    Not in our library10.1073/pnas.1010030108

  115. 115.

    Lader CS, Flanagan AM. Prostaglandin E2, interleukin and tumor necrosis factor-α increase human osteoclast formation and bone resorption in vitro. Endocrinology. 1998;139(7):3157-3164.

    Not in our library10.1210/endo.139.7.6085

  116. 116.

    O' Gradaigh D, Ireland D, Bord S, Compston JE. Joint erosion in rheumatoid arthritis: Interactions between tumour necrosis factor α, interleukin 1, and receptor activator of nuclear factor κB ligand (RANKL) regulate osteoclasts. Annals of the Rheumatic Diseases. 2004;63(4):354-359.

    Not in our library10.1136/ard.2003.008458

  117. 117.
    Immunological Reaction in TNF- α -Mediated Osteoclast Formation and Bone Resorption In Vitro and In Vivo · 2013
    No notice
  118. 118.

    Li P, Schwarz EM, O'Keefe RJ, Ma L, Boyce BF, Xing L. RANK signaling is not required for TNFα-mediated increase in CD11bhi osteoclast precursors but is essential for mature osteoclast formation in TNFα-mediated inflammatory arthritis. Journal of Bone and Mineral Research. 2004;19(2):207-213.

    Not in our library10.1359/jbmr.0301233

  119. 119.

    Neidel J, Schulze M, Lindschau J. Association between degree of bone-erosion and synovial fluid-levels of tumor necrosis factor α in the knee-joints of patients with rheumatoid arthritis. Inflammation Research. 1995;44(5):217-221.

    Not in our library10.1007/bf01782262

  120. 120.

    Ma T, Miyanishi K, Suen A, et al. Human interleukin-1-induced murine osteoclastogenesis is dependent on RANKL, but independent of TNF-α. Cytokine. 2004;26(3):138-144.

    Not in our library10.1016/j.cyto.2004.02.001

  121. 121.

    Lee S, Gardner AE, Kalinowski JF, Jastrzebski SL, Lorenzo JA. RANKL-stimulated osteoclast-like cell formation in vitro is partially dependent on endogenous interleukin-1 production. Bone. 2006;38(5):678-685.

    Not in our library10.1016/j.bone.2005.10.011

  122. 122.

    Tanabe N, Maeno M, Suzuki N, et al. IL-1α stimulates the formation of osteoclast-like cells by increasing M-CSF and PGE2 production and decreasing OPG production by osteoblasts. Life Sciences. 2005;77(6):615-626.

    Not in our library10.1016/j.lfs.2004.10.079

  123. 123.

    Heymann D, Rousselle A. gp130 cytokine family and bone cells. Cytokine. 2000;12(10):1455-1468.

    Not in our library10.1006/cyto.2000.0747

  124. 124.

    Liu XH, Kirschenbaum A, Yao S, Levine AC. The role of the interleukin-6/gp130 signaling pathway in bone metabolism. Vitamins and Hormones. 2006;74:341-355.

    Not in our library10.1016/s0083-6729(06)74014-6

  125. 125.

    Wong PKK, Campbell IK, Egan PJ, Ernst M, Wicks IP. The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis and Rheumatism. 2003;48(5):1177-1189.

    Not in our library10.1002/art.10943

  126. 126.

    Steeve KT, Marc P, Sandrine T, Dominique H, Yannick F. IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine and Growth Factor Reviews. 2004;15(1):49-60.

    Not in our library10.1016/j.cytogfr.2003.10.005

  127. 127.

    Kim S, Yamazaki M, Shevde NK, Pike JW. Transcriptional control of receptor activator of nuclear factor-κB ligand by the protein kinase A activator forskolin and the transmembrane glycoprotein 130-activating cytokine, oncostatin M, is exerted through multiple distal enhancers. Molecular Endocrinology. 2007;21(1):197-214.

    Not in our library10.1210/me.2006-0315

  128. 128.

    O'Brien CA, Gubrij I, Lin S, Saylors RL, Manolagas SC. STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-κB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone. The Journal of Biological Chemistry. 1999;274(27):19301-19308.

    Not in our library10.1074/jbc.274.27.19301

  129. 129.

    Yokota K, Sato K, Miyazaki T, Kitaura H, Kayama H, Miyoshi F. Combination of tumor necrosis factor alpha and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo. Arthritis & Rheumatology. 2014;66(1):121-129.

    Not in our library10.1002/art.38218

  130. 130.

    Wallace A, Cooney TE, Englund R, Lubahn JD. Effects of interleukin-6 ablation on fracture healing in mice. Journal of Orthopaedic Research. 2011;29(9):1437-1442.

    Not in our library10.1002/jor.21367

  131. 131.

    Yang X, Ricciardi BF, Hernandez-Soria A, Shi Y, Pleshko Camacho N, Bostrom MPG. Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice. Bone. 2007;41(6):928-936.

    Not in our library10.1016/j.bone.2007.07.022

  132. 132.

    Rozen N, Lewinson D, Bick T, Jacob ZC, Stein H, Soudry M. Fracture repair: modulation of fracture-callus and mechanical properties by sequential application of IL-6 following PTH 1-34 or PTH 28-48. Bone. 2007;41(3):437-445.

    Not in our library10.1016/j.bone.2007.04.193

  133. 133.

    Duplomb L, Baud'huin M, Charrier C, et al. Interleukin-6 inhibits receptor activator of nuclear factor κB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage: key role of serine727 phosphorylation of signal transducer and activator of transcription 3. Endocrinology. 2008;149(7):3688-3697.

    Not in our library10.1210/en.2007-1719

  134. 134.

    Honda K. Interleukin-6 and soluble interleukin-6 receptor suppress osteoclastic differentiation by inducing PGE(2) production in chondrocytes. Journal of Oral Science. 2011;53(1):87-96.

    Not in our library10.2334/josnusd.53.87

  135. 135.

    Darowish M, Rahman R, Li P, et al. Reduction of particle-induced osteolysis by interleukin-6 involves anti-inflammatory effect and inhibition of early osteoclast precursor differentiation. Bone. 2009;45(4):661-668.

    Not in our library10.1016/j.bone.2009.06.004

  136. 136.

    Kotake S, Udagawa N, Takahashi N, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. Journal of Clinical Investigation. 1999;103(9):1345-1352.

    Not in our library10.1172/jci5703

  137. 137.

    Van Bezooijen RL, Papapoulos SE, Löwik CWGM. Effect of interleukin-17 on nitric oxide production and osteoclastic bone resorption: is there dependency on nuclear factor-κB and receptor activator of nuclear factor κB (RANK)/RANK ligand signaling? Bone. 2001;28(4):378-386.

    Not in our library10.1016/s8756-3282(00)00457-9

  138. 138.

    Kelchtermans H, Schurgers E, Geboes L, et al. Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of interferon-γ and counteraction by interferon-γ. Arthritis Research and Therapy. 2009;11(4, article R122).

    Not in our library10.1186/ar2787

  139. 139.

    Van Bezooijen RL, Farih-Sips HCM, Papapoulos SE, Löwik CWGM. Interleukin-17: a new bone acting cytokine in vitro. Journal of Bone and Mineral Research. 1999;14(9):1513-1521.

    Not in our library10.1359/jbmr.1999.14.9.1513

  140. 140.

    Yago T, Nanke Y, Ichikawa N, et al. IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-α antibody: a novel mechanism of osteoclastogenesis by IL-17. Journal of Cellular Biochemistry. 2009;108(4):947-955.

    Not in our library10.1002/jcb.22326

  141. 141.

    Oostlander AE, Everts V, Schoenmaker T, et al. T cell-mediated increased osteoclast formation from peripheral blood as a mechanism for crohn's disease-associated bone loss. Journal of Cellular Biochemistry. 2012;113(1):260-268.

    Not in our library10.1002/jcb.23352

  142. 142.

    Lubberts E, van den Bersselaar L, Oppers-Walgreen B, et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-κB ligand/osteoprotegerin balance1. Journal of Immunology. 2003;170(5):2655-2662.

    Not in our library10.4049/jimmunol.170.5.2655

  143. 143.

    Deselm CJ, Takahata Y, Warren J, et al. IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. Journal of Cellular Biochemistry. 2012;113(9):2895-2902.

    Not in our library10.1002/jcb.24165

  144. 144.
    Estrogen Deficiency Induces the Differentiation of IL-17 Secreting Th17 Cells: A New Candidate in the Pathogenesis of Osteoporosis · 2012
    No notice
  145. 145.

    Balani D, Aeberli D, Hofstetter W, Seitz M. Interleukin-17A stimulates granulocyte-macrophage colony-stimulating factor release by murine osteoblasts in the presence of 1,25-dihydroxyvitamin D 3 and inhibits murine osteoclast development in vitro. Arthritis and Rheumatism. 2013;65(2):436-446.

    Not in our library10.1002/art.37762

  146. 146.

    Kitami S, Tanaka H, Kawato T, et al. IL-17A suppresses the expression of bone resorption-related proteinases and osteoclast differentiation via IL-17RA or IL-17RC receptors in RAW264.7 cells. Biochimie. 2010;92(4):398-404.

    Not in our library10.1016/j.biochi.2009.12.011

  147. 147.

    Adamopoulos IE, Tessmer M, Chao C, et al. IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. Journal of Immunology. 2011;187(2):951-959.

    Not in our library10.4049/jimmunol.1003986

  148. 148.

    Ji HJ, Cho M, Moon Y, et al. IL-23 induces receptor activator of NF-κB ligand expression on CD4+ T cells and promotes osteoclastogenesis in an autoimmune arthritis model. Journal of Immunology. 2008;181(2):1507-1518.

    Not in our library10.4049/jimmunol.181.2.1507

  149. 149.

    Hu Y, Xiong H, Peng B. Expression of a cytokine, interleukin-23, in experimental periapical lesions. International Endodontic Journal. 2013;46(10):896-903.

    Not in our library10.1111/iej.12077

  150. 150.

    Chen L, Wei X, Evans B, Jiang W, Aeschlimann D. IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-κB (RANK) expression in myeloid precursor cells. European Journal of Immunology. 2008;38(10):2845-2854.

    Not in our library10.1002/eji.200838192

  151. 151.

    Kamiya S, Nakamura C, Fukawa T, et al. Effects of IL-23 and IL-27 on osteoblasts and osteoclasts: inhibitory effects on osteoclast differentiation. Journal of Bone and Mineral Metabolism. 2007;25(5):277-285.

    Not in our library10.1007/s00774-007-0766-8

  152. 152.

    Binder NB, Puchner A, Niederreiter B, et al. Tumor necrosis factor-inhibiting therapy preferentially targets bone destruction but not synovial inflammation in a tumor necrosis factor-driven model of rheumatoid arthritis. Arthritis and Rheumatism. 2013;65(3):608-617.

    Not in our library10.1002/art.37797

  153. 153.

    Redlich K, Görtz B, Hayer S, et al. Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis. The American Journal of Pathology. 2004;164(2):543-555.

    Not in our library10.1016/s0002-9440(10)63144-6

  154. 154.

    Saidenberg-Kermanac'h N, Corrado A, Lemeiter D, Devernejoul MC, Boissier MC, Cohen-Solal ME. TNF-α antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone. 2004;35(5):1200-1207.

    Not in our library10.1016/j.bone.2004.07.004

  155. 155.

    Kitazawa R, Kimble RB, Vannice JL, Kung VT, Pacifici R. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. The Journal of Clinical Investigation. 1994;94(6):2397-2406.

    Not in our library10.1172/jci117606

  156. 156.

    Kimble RB, Bain S, Pacifici R. The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. Journal of Bone and Mineral Research. 1997;12(6):935-941.

    Not in our library10.1359/jbmr.1997.12.6.935

  157. 157.

    Feige U, Hu YL, Gasser J, Campagnuolo G, Munyakazi L, Bolon B. Anti-interleukin-1 and anti-tumor necrosis factor-α synergistically inhibit adjuvant arthritis in lewis rats. Cellular and Molecular Life Sciences. 2000;57(10):1457-1470.

    Not in our library10.1007/pl00000629

  158. 158.

    Shealy DJ, Wooley PH, Emmell E, et al. Anti-TNF-alpha antibody allows healing of joint damage in polyarthritic transgenic mice. Arthritis Research. 2002;4(5):p. R7.

    Not in our library10.1186/ar430

  159. 159.

    Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. The Lancet. 2007;370(9602):1861-1874.

    Not in our library10.1016/s0140-6736(07)60784-3

  160. 160.

    Mertens M, Singh JA. Anakinra for rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2009;(1).

    Not in our library10.1002/14651858.cd005121.pub3

  161. 161.

    Bresnihan B, Alvaro-Gracia JM, Cobby M. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis and Rheumatism. 1998;41(12):2196-2204.

    Not in our library10.1002/1529-0131(199812)41:12<2196::aid-art15>3.0.co;2-2

  162. 162.

    Tanaka K, Hashizume M, Mihara M, Yoshida H, Suzuki M, Matsumoto Y. Anti-interleukin-6 receptor antibody prevents systemic bone mass loss via reducing the number of osteoclast precursors in bone marrow in a collagen-induced arthritis model. Clinical and Experimental Immunology. 2014;175(2):172-180.

    Not in our library10.1111/cei.12201

  163. 163.

    Axmann R, Böhm C, Krönke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis and Rheumatism. 2009;60(9):2747-2756.

    Not in our library10.1002/art.24781

  164. 164.

    Finzel S, Rech J, Schmidt S, Engelke K, Englbrecht M, Schett G. Interleukin-6 receptor blockade induces limited repair of bone erosions in rheumatoid arthritis: a micro CT study. Annals of the Rheumatic Diseases. 2013;72(3):396-400.

    Not in our library10.1136/annrheumdis-2011-201075

  165. 165.

    Terpos E, Fragiadaki K, Konsta M, Bratengeier C, Papatheodorou A, Sfikakis PP. Early effects of IL-6 receptor inhibition on bone homeostasis: a pilot study in women with rheumatoid arthritis. Clinical and Experimental Rheumatology. 2011;29(6):921-925.

    Not in our library

  166. 166.

    Zwerina K, Koenders M, Hueber A, et al. Anti IL-17A therapy inhibits bone loss in TNF-α-mediated murine arthritis by modulation of the T-cell balance. European Journal of Immunology. 2012;42(2):413-423.

    Not in our library10.1002/eji.201141871

  167. 167.

    Koenders MI, Lubberts E, Oppers-Walgreen B, et al. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. The American Journal of Pathology. 2005;167(1):141-149.

    Not in our library10.1016/s0002-9440(10)62961-6

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