Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 18, 2026.

Regulation of Osteoblast Differentiation by Cytokine Networks

Dulshara Sachini Amarasekara, Sumi Kim, Jaerang Rho

International Journal of Molecular Sciences · 2021 · Review · CC BY

doi:10.3390/ijms22062851

Abstract

Osteoblasts, which are bone-forming cells, play pivotal roles in bone modeling and remodeling. Osteoblast differentiation, also known as osteoblastogenesis, is orchestrated by transcription factors, such as runt-related transcription factor 1/2, osterix, activating transcription factor 4, special AT-rich sequence-binding protein 2 and activator protein-1. Osteoblastogenesis is regulated by a network of cytokines under physiological and pathophysiological conditions. Osteoblastogenic cytokines, such as interleukin-10 (IL-10), IL-11, IL-18, interferon-γ (IFN-γ), cardiotrophin-1 and oncostatin M, promote osteoblastogenesis, whereas anti-osteoblastogenic cytokines, such as tumor necrosis factor-α (TNF-α), TNF-β, IL-1α, IL-4, IL-7, IL-12, IL-13, IL-23, IFN-α, IFN-β, leukemia inhibitory factor, cardiotrophin-like cytokine, and ciliary neurotrophic factor, downregulate osteoblastogenesis. Although there are gaps in the body of knowledge regarding the interplay of cytokine networks in osteoblastogenesis, cytokines appear to be potential therapeutic targets in bone-related diseases. Thus, in this study, we review and discuss our osteoblast, osteoblast differentiation, osteoblastogenesis, cytokines, signaling pathway of cytokine networks in osteoblastogenesis.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Background

Bone modeling initially occurs during development, where there are two modes of bone development: intramembranous ossification and endochondral ossification. In intramembranous ossification, mesenchymal tissues are directly converted to bone, while in endochondral ossification, mesenchymal tissues are differentiated into cartilage before being replaced by bone. Bone remodeling is a life-long process in which the volume of bone resorbed by osteoclasts (OCs) is restored by bone-forming osteoblasts (OBs). A balance between OC and OB activity is crucial in maintaining physiological bone turnover rates, and a flaw in this balance can lead to debilitating bone diseases, such as rheumatoid arthritis (RA), periodontal diseases, and osteoporosis. Thus, maintaining the biomechanical integrity of bone by either modeling or remodeling is a complex process regulated by numerous cell lineages, transcription regulation, a network of cytokines, and growth factors. Adequate understanding of the regulation of OC and OB activity in bone tissue is crucial for the development of novel therapeutics to manage bone-related diseases. We have previously reviewed the role played by cytokines in regulating OC differentiation, also known as osteoclastogenesis, under physiological and pathophysiological conditions. In this article, we review the current knowledge of the impact of cytokines in OB differentiation, also known as osteoblastogenesis.

2. OB Differentiation and Function

OBs, which are bone-forming cells, are small mononucleated cells of mesenchymal stem cell (MSC) origin. OBs are usually cuboid in shape but can be found in morphologically diverse round, flat and cylindrical forms. The sequential action of cytokine networks and transcription factors results in the differentiation of OB lineage cells from mesenchymal precursors (Figure 1).

OB lineage progenitor cells undergo three developmental stages: (1) cell proliferation, (2) extracellular matrix (ECM) secretion and matrix maturation and (3) matrix mineralization. Following OB lineage commitment, pre-OBs undergo active proliferation and express collagen, fibronectin, osteopontin (OPN) and transforming growth factor-β (TGF-β) receptor 1. In the second stage, cell proliferation is downregulated, and immature OBs differentiate into mature OBs that secrete collagen type 1 alpha 1 chain (COL1A1) as the major constituent of the ECM and express alkaline phosphatase (ALP) to mature the ECM. Upon completion of matrix maturation, matrix mineralization occurs in a highly ordered process via the expression of various osteoblastogenic markers, such as OPN, osteocalcin (OCN), and bone sialoprotein (BSP), with continued expression of ALP and COL1A1. OCN regulates calcium metabolism and promotes the deposition of minerals in the ECM, OPN promotes bone formation and mineralization, and BSP promotes mineralization regulating hydroxyapatite crystal formation. Finally, mature OBs undergo apoptosis, become bone-lining cells or progressively incorporate into the bone matrix as terminally differentiated osteocytes (OSs).

OBs orchestrate the bone remodeling process by regulating bone-resorbing OC differentiation and function through the production of two essential cytokines: receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The binding of RANKL and M-CSF to receptors RANK and c-fms, respectively, on the surface of OC progenitors, induces a number of downstream signaling cascades, ultimately activating nuclear factor of activated T cells c1, a master transcription factor of osteoclastogenesis, leading to enhanced OC differentiation, proliferation and survival. Moreover, OBs secrete osteoprotegerin (OPG), a key negative regulator of osteoclastogenesis that binds with RANKL, thereby hindering RANKL-RANK interaction. Therefore, OBs are vital for maintaining balance in bone homeostasis by regulating the RANK/RANKL/OPG axis.

3. Transcriptional Regulation in Osteoblastogenesis

Osteoblastogenesis is regulated by multiple cytokines and hormone signaling cascades, resulting in subsequent activation of downstream transcription factors. Among the downstream transcription factors, runt-related related transcription factor 2 (RUNX2/CBFA1/AML3/PEBP2αA) acts as the master transcription factor leading to the expression of osteoblastogenic markers, such as ALP, OCN, OPN, osteonectin (ONN), BSP, and COL1A1, in osteoblastogenesis. Runx2-deficient mice exhibit defects in endochondral and intramembranous bone formation. In osteoblastogenesis, RUNX2 is marginally expressed in uncommitted MSCs and elevated throughout the proliferation of pre-OBs. RUNX2 level peaks at the immature OB stage and decreases in the maturation stage. RUNX2 enhances the expression of osterix (OSX/Sp7), an essential transcription factor for OB commitment and differentiation. OSX can induce the expression of ALP, OCN, OPN, ONN, BSP, and COL1A1. Osx-deficient mice also exhibit defects in bone formation due to the complete loss of OBs. However, RUNX2 expression remains unaltered in Osx-deficient mice, demonstrating that RUNX2 is upstream of OSX in osteoblastogenesis. The number of OB progenitors and their proliferation was lower in the calvariae of Runx2-deficient mice, whereas Osx-deficient mice had OB progenitors in abundance with adequate proliferation, demonstrating that RUNX2 is required for the expansion of OB progenitors. Consequently, the transcription factors RUNX2 and OSX are of high importance in osteoblastogenesis.

Activating transcription factor 4 (ATF4), belonging to the cAMP-responsive element-binding (CREB) protein family of transcription factors, is another crucial transcription factor in osteoblastogenesis. ATF4 promotes osteoblastogenesis through direct interaction with RUNX2 to enhance OCN expression. ATF4-deficient mice are reported to have severe osteoporosis, osteodysplasty, and altered bone mineralization with impaired terminal differentiation of OBs, probably due to reduced expression of COL1A1, OCN, and BSP. Moreover, ATF4 can promote osteoblastogenesis indirectly by modulating β-catenin levels in MSCs. Thus, ATF4 expression is limited in committed OB lineage cells, whereas RUNX2 and OSX are more broadly expressed from OB lineage commitment to maturation during osteoblastogenesis (Figure 1). Taken together, ATF4 is a direct or indirect transcriptional regulator of osteoblastogenic marker expression in osteoblastogenesis.

A recent study implicated RUNX1 in promoting endochondral ossification and osteoblastogenesis. RUNX1 is expressed at all stages in OB lineage cells. In a conditional knockout study of Runx1flox/flox/Osx-Cre mice, RUNX 1 deficiency resulted in decreased bone density by downregulating RUNX2, OSX, and ATF4 expression in OB lineage cells. It was also determined that RUNX1 promotes RUNX2 and OCN expression by directly binding to the promoter regions of the RUNX2 and OCN genes. Furthermore, RUNX1 can improve OB lineage commitment and promote bone formation by upregulating the bone morphogenetic protein-7 (BMP-7) and Wnt/β-catenin pathways. Therefore, RUNX1 has emerged as a novel regulator of osteoblastogenesis.

A crucial role of activator protein-1 (AP-1) and special AT-rich sequence-binding protein 2 (SATB2) in OB differentiation and function is also evident from previous studies. AP-1 is a dimeric transcription factor that is primarily composed of c-jun, c-fos, and ATF family dimers. AP-1 activation is induced by stimulation of osteoblastogenic factors, such as parathyroid hormone (PTH), TGF-β and vitamin D, in osteoblastogenesis. Deficiency of c-fos and ATF members in mice has highlighted their importance in OB differentiation and function. Other AP-1 members, such as Fra-1, Fra-2, and ΔFosB (FosB2), are implicated in promoting OB differentiation and function. SATB2 is also implicated in promoting OB differentiation and bone regeneration by inducing RUNX2/ATF4-mediated expression of osteoblastogenic markers, such as OCN and BSP. In addition, SATB2-deficient mice exhibit defects in OB differentiation and function, leading to delayed bone formation and mineralization. A recent study also demonstrated that SATB2 promotes OB progenitor proliferation.

4. Signaling Pathways in Osteoblastogenesis

Osteoblastogenesis is regulated by multiple signaling pathways, including Wnt, PTH, BMP, TGF-β, fibroblast growth factor (FGF), and hedgehog (Hh) (Figure 2). The Wnt signaling pathway plays a pivotal role in promoting OB differentiation, proliferation, and maturation. Wnt signaling can be categorized into two pathways: the canonical Wnt pathway and the non-canonical pathway. The canonical Wnt pathway, also called the Wnt/β-catenin-dependent pathway, is best understood for its role in bone regeneration and repair. In osteoblastogenesis, Wnt ligand binding to its receptors activates downstream signaling cascades, resulting in β-catenin translocation into the nucleus, thereby enhancing osteoblastogenic target gene expression (Figure 2). In the absence of Wnt ligand binding (or inactive state), β-catenin is phosphorylated by β-catenin destruction complex proteins, including axin, adenomatous polyposis coli, glycogen synthase kinase-3 β, and casein kinase-1. Phosphorylated β-catenin is ubiquitinated by β-TrCP ubiquitin E3 ligase and degraded by the ubiquitin-dependent proteasomal system (Figure 2). Non-canonical Wnt signaling induced by Wnt5a or Wnt11 binding to a receptor complex consisting of frizzled and the receptor tyrosine kinase-like orphan receptor (ROR) coreceptor transduces signals through c-jun N-terminal kinase (JNK) activation to induce RUNX2 (Figure 2). Wnt5a-deficient mice had low OB numbers and reduced bone mass, indicating that Wnt5a is important for MSC lineage commitment to OB differentiation. The Wnt/calcium pathway, one of the non-canonical Wnt signaling pathways, increases intracellular calcium levels to activate calmodulin-dependent kinase II, protein kinase C (PKC), and calcineurin, leading to the induction of AP-1 transcription factors (Figure 2).

BMPs belong to the TGF-β superfamily and are reported to be osteoblastogenic factors. In particular, it has been well-documented that BMP-2 is a potent inducer of osteoblastogenesis by activating the Smad signaling pathway. BMPs bind to serine/threonine kinase receptor II and activate receptor I to transmit signals through Smad1/5/8 (Figure 2). Smad1/5/8 complexed with Smad4 is translocated to the nucleus to activate RUNX2, leading to enhanced expression of osteoblastogenic markers. Moreover, treatment with antagonistic antibodies against BMP-2, -4, and -7 can downregulate the expression of osteoblastogenic markers, such as ALP, OCN, and BSP, revealing that BMP-mediated signaling is crucial for RUNX2-mediated osteoblastogenesis. BMP-2/Smad signaling is also reported to induce OSX through distal-less homeobox 5 (DLX5) induction in a RUNX2-independent manner. In the cranial structure of the mesenchyme, DLX5 is reported to induce osteoblastogenesis by inducing RUNX2-mediated ALP and OPN expression, revealing that DLX5 is an upstream regulator of RUNX2.

TGF-β can directly induce osteoblastogenesis from OB progenitor cells. The ability of TGF-β to enhance OB proliferation, inhibit OB apoptosis, recruit OB precursors to the bone-forming site and produce ECM during osteoblastogenesis has been well-documented. TGF-β binding to TGFβRI and TGFβRII triggers downstream signaling through Smad2/3 (Figure 2). Activated Smad2/3 forms a complex with Smad4 and undergoes nuclear translocation to induce RUNX2-mediated osteoblastogenic gene expression. Moreover, TGF-β and BMPs can induce TGF-β activation kinase 1 to activate RUNX2 through the mitogen-activated protein kinase (MAPK) signaling pathway.

The FGF/FGF receptor (FGFR)-mediated signaling cascade regulates OB progenitor proliferation, maturation, and apoptosis. FGF/FGFR signaling is reported to induce RUNX2 activation, leading to enhanced expression of osteoblastogenic markers, such as ALP, OCN, and COL1A1, through downstream signaling of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), phospholipase γ/PKCα and extracellular receptor kinase (ERK)1/2 (Figure 2). FGF2-deficient mice exhibit decreased bone mass and bone formation, and FGF18-deficient mice show delayed ossification. Moreover, FGFR2-deficient mice with conditional deletion of FGFR2 exhibit decreased bone formation and reduced proliferation of OB progenitor cells.

PTH is a positive regulator of osteoblastogenesis. PTH induces the proliferation of OB progenitor cells, OB lineage commitment, and maturation in osteoblastogenesis. PTH binding to the PTH receptor induces cAMP/PKA downstream signaling to phosphorylate and activate CREB, a member of a large family of basic leucine zipper domain DNA-binding proteins (Figure 2). Activated CREB induces the expression of osteoblastogenic markers, such as OCN and BSP, leading to bone formation. Moreover, PTH-activated CREB effectively induces BMP-2 expression. Mice with a conditional deletion of the G-protein coupled type 1 PTH receptor in OBs exhibit disrupted trabecular bone formation resulting from reduced OB activity.

Hh signaling is involved in promoting osteoblastogenesis. Hh signaling activates glioma-associated oncogene (Gli) transcription factors by releasing the membrane protein smoothened, which triggers signaling cascade, and the activated Gli transcription factor travels to the nucleus to stimulate RUNX2/OSX activation in osteoblastogenesis (Figure 2). In rat MSCs, Hh also induces OB proliferation and differentiation by RUNX2-induced ALP, OCN, and COL1A1 expression. Moreover, Hh and BMP synergistically induce osteoblastogenesis in the endochondral skeleton.

5. Cytokine Regulation of Osteoblastogenesis

Osteoblastogenesis is tightly regulated by complex cytokine networks under physiological and pathophysiological conditions. Osteoblastogenic cytokines, such as interleukin-10 (IL-10), IL-11, IL-18, interferon-γ (IFN-γ), cardiotrophin-1 (CT-1), and oncostatin M (OSM), promote osteoblastogenesis, whereas anti-osteoblastogenic cytokines, such as tumor necrosis factor-α (TNF-α), TNF-β, IL-1α, IL-4, IL-7, IL-12, IL-13, IL-23, IFN-α, IFN-β, leukemia inhibitory factor (LIF), cardiotrophin-like cytokine (CLC) and ciliary neurotrophic factor (CNTF), downregulate osteoblastogenesis (Table 1).

TNF-α is a proinflammatory cytokine that plays an important role in bone diseases. TNF-α inhibits RUNX2 expression and RUNX2-induced osteoblastogenic marker expression in OB precursors and MC3T3-E1 preosteoblastic cells. TNF-α blocks osteoblastogenic marker expression by osteoblastogenic mediator β-glycerophosphate-induced RUNX2 activation via the TNF type 1 receptor. TNF-α is also reported to inhibit BMP-induced osteoblastogenesis by activating JNK signaling and suppressing BMP/Smad signaling. In addition, the expression of nephronectin, an extracellular matrix protein considered to be a positive regulator of osteoblastogenesis, is suppressed by TNF-α in MC3T3-E1 preosteoblastic cells. TNF-α abrogates OB lineage commitment in osteoblastogenesis by increasing ubiquitin E3 ligase Wwp1 expression, leading to proteasomal degradation of the AP-1 transcription factor. TNF-α also inhibits the expression of osteoblastogenic transcription factor SATB2 via the BMP/Smad, NF-κB and MAPK signaling pathways in osteoblastogenesis. In estrogen deficiency-induced osteoporosis, TNF-α inhibits OB proliferation and differentiation by upregulating P2YR expression via the ERK/JNK signaling pathways. In addition to TNF-α, a recent study reported that TNF-β inhibits the early stage of osteoblastogenic differentiation from MSCs by downregulating RUNX2 and activating NF-κB. Taken together, TNF-α and TNF-β are known to be strong anti-osteoblastogenic cytokines.

IL-1 is a potent proinflammatory cytokine that exists in two forms: IL-1α and IL-1β. IL-1α induces OB apoptosis and inhibits osteoblastogenesis by activating the JNK/p38 MAPK pathway, while IL-1β induces OB differentiation from MSCs and matrix mineralization through activation of the non-canonical Wnt (Wnt5a/ROR2) signaling pathway. However, inhibitory functions of IL-1β in OB differentiation and bone formation were also reported. Under inflammatory conditions, IL-1β and TNF-α are reported to suppress OB differentiation from MSCs and matrix mineralization by downregulating osteoblastogenic markers, such as RUNX2, OSX, ALP, and COL1A1. IL-18, a proinflammatory cytokine belonging to the IL-1 family, acts as a mitogen in OB proliferation. IL-37, an anti-inflammatory cytokine belonging to the IL-1 family, promotes osteoblastogenesis by inducing osteoblastogenic markers, such as RUNX2, ALP, OCN, and COL1A1, by activating the PI3K/AKT pathway. In contrast, the anti-osteoblastogenic role of IL-37, which suppresses BMP-2 and ALP expression, has been documented in chronic inflammatory conditions, such as calcific aortic valve disease. Thus, IL-1 family cytokines play important roles in osteoblastogenesis, depending on physiological and pathophysiological status.

IL-3 is a multicolony stimulating factor produced by T cells. In osteoblastogenesis, IL-3 induces OB differentiation and matrix mineralization by activating RUNX2 and OSX, leading to the expression of osteoblastogenic markers, such as ALP, OPN, OCN, and COL1A1. IL-3 indirectly induces osteoblastogenesis by inducing BMP-2 expression through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT) signaling pathway. In contrast, it has been reported that BMP-2-mediated osteoblastogenesis is inhibited in multiple myeloma patients with high IL-3 levels. Thus, IL-3 plays an important role in osteoblastogenesis depending on physiological and pathophysiological status.

IL-4 is an anti-inflammatory cytokine that shares some biological similarities with IL-13. IL-4 and IL-13 inhibit osteoblastogenesis by downregulating PTH-induced ALP activity in MC3T3-E1 preosteoblastic cells. IL-4 and IL-13 also inhibit the proliferation of human OBs and induce IL-6 production in these cells to regulate OC recruitment. IL-4 inhibits ALP expression and matrix mineralization in MC3T3 preosteoblastic cells. Taken together, these findings indicate that IL-4 and IL-13 are anti-osteoblastogenic cytokines.

The IL-6 family of cytokines consists of IL-6, IL-11, OSM, CT-1, LIF, CLC, and CNTF. In murine calvarial OBs and MC3T3-E1 preosteoblastic cells, IL-6 inhibits osteoblastogenesis and matrix mineralization by downregulating osteoblastogenic markers, such as RUNX2, OSX, and OCN. Moreover, IL-6 depletion increases BMP2/7-induced osteoblastogenesis in KS483 preosteoblastic cells. In contrast, in periodontal ligament cells, IL-6 exerts osteoblastogenic effects by enhancing RUNX2 and ALP expression. IL-6 also increases ALP activity and matrix mineralization in human adipose stem cells. Moreover, IL-6 accelerates matrix mineralization through STAT3-dependent ROR2 induction in human adipose tissue-derived MSCs. Thus, the functional role of IL-6 in osteoblastogenesis is still controversial.

The IL-6 family member IL-11 is produced in response to IL-1, TNF-α, TGF-β, PTH, and mechanical stress in OB lineage cells. IL-11 induces osteoblastogenesis by suppressing Dickkopf1/2 inhibitors of Wnt signaling. Moreover, IL-11 induces osteoblastogenesis synergistically with BMP-2 by increasing osteoblastogenic markers, such as ALP, OCN, BSP and PTH receptor. Similarly, OSM directly stimulates OB commitment from MSCs, OB differentiation, and matrix mineralization by suppressing sclerostin, a potent inhibitor of bone formation secreted by OSs. CT-1 is capable of increasing OB activity through the activation of RUNX2, CAAT/enhancer-binding protein-δ (C/EBP-δ) and C/EBP-β. Moreover, CT-1-deficient mice showed reduced OB numbers. However, the IL-6 family member LIF inhibits osteoblastogenesis at the early stages through the STAT3 signaling pathway. LIF receptor overexpression in human MSCs suppresses osteoblastogenesis by downregulating RUNX2, ALP, and ONN, while LIF receptor depletion by siRNA knockdown enhances osteoblastogenesis. The IL-6 family member CLC1 is reported to prevent OB differentiation from MSCs and matrix mineralization through STAT1/3 signaling pathways. CNTF, another member of the IL-6 family of cytokines, inhibits matrix mineralization and OSX expression in OBs. CNTF-deficient mice exhibited increased OB numbers and high mineralization rates. Moreover, myogenic CNTF suppresses the expression of osteoblastogenic markers, such as RUNX2, OSX, ALP, OCN, and PTH receptors, in murine calvarial OBs. Taken together, in the IL-6 family members, IL-11, OSM, and CT-1 exert osteoblastogenic effects, while LIF, CLC, and CNTF are anti-osteoblastogenic cytokines.

IL-7 is a crucial cytokine in B and T cell lymphopoiesis. It has been reported that direct injection of IL-7 in mice inhibits bone formation. In periodontal ligament stem cells, IL-7 suppresses osteoblastogenesis by downregulating osteoblastogenic markers, such as RUNX2, OSX, ALP, and OCN, through the inactivation of the MAPK pathway. In multiple myeloma, IL-7 is implicated in inhibiting bone formation by suppressing RUNX2 activity. Moreover, in estrogen deficiency, IL-7 inhibits osteoblastogenesis by reducing RUNX2 activation. Thus, IL-7 is a potent inhibitor of osteoblastogenesis in both physiological and pathophysiological states.

IL-10 is an anti-inflammatory cytokine. The osteoblastogenic properties of IL-10 are less thoroughly documented than those of other cytokines. Low physiological concentrations of IL-10 induce osteoblastogenesis by activating the p38 MAPK signaling pathway in human MSCs, while higher pathological doses of IL-10 inhibit osteoblastogenesis by activating NF-κB signaling. Moreover, IL-10-deficient mice exhibit reduced bone formation. Thus, IL-10 can be considered a potential osteoblastogenic cytokine.

IL-12 and IL-23 are proinflammatory cytokines belonging to the IL-12 family. IL-12p40-deficient mice, defective in both IL-12 and IL-23, have been reported to have enhanced bone formation in the distal femur. Moreover, IL-12 and IL-23 indirectly inhibit osteoblastogenesis by stimulating CD4+ T cells. Enhanced bone formation IL-12p40-deficient mice was protective against age-related bone loss. Collectively, IL-12 and IL-23 are potential anti-osteoblastogenic cytokines.

IL-15 is a proinflammatory cytokine that shares most of its biological activities with IL-2. Elevated levels of IL-15 have been reported in inflammatory bone diseases, such as RA and periodontal disease. IL-15 stimulates apoptosis of OBs via activation of NK cells. However, IL-15Rα deficiency decreases OB function and bone mineralization. Thus, the role of IL-15 in osteoblastogenesis remains controversial.

IL-17 is a proinflammatory cytokine predominantly produced by T helper 17 (Th17) cells, dendritic cells, and other immune cells. It has been reported that OB maturation is stimulated by proinflammatory Th17 cells. IL-17 produced by Th17 cells induces OB maturation of human MSCs. Furthermore, IL-17 exhibits synergistic effects with BMP-2 in matrix mineralization and bone formation. In a recent study, IL-17 was implicated in accelerating OB differentiation, matrix mineralization, and proliferation in mouse calvarial OBs. Osteogenic differentiation of MSCs induced by IL-17 is further enhanced by coculture with OSs, indicating that IL-17 alters the MSC niche to induce osteoblastogenesis in cooperation with OSs. In ankylosing spondylosis, IL-17 induces osteoblastogenesis by activating the JAK2/STAT3 pathway. In contrast, IL-17 has been reported to inhibit osteoblastogenesis in rat calvarial OB precursors, with reduced expression of OSX, ALP, and OCN. Similarly, an inhibitory effect of IL-17 on calvarial OB differentiation via regulation of canonical Wnt signaling pathway components has been reported in a spondyloarthritis model. Furthermore, IL-17 inhibited BMP-2-induced osteoblastogenesis by downregulating osteoblastogenic markers, such as RUNX2, ALP, and OCN. Thus, the role of IL-17 in osteoblastogenesis is still controversial.

IFN-γ is a well-known inhibitor of OC differentiation, but its role in osteoblastogenesis is also documented. IFN-γ promotes osteoblastogenesis by inducing the expression of osteoblastogenic markers, such as RUNX2, OSX, ALP, and OCN. IFN-γ deficiency or knockdown in human MSCs inhibits osteoblastogenesis by downregulating RUNX2 expression. Moreover, IFN-γ receptor-deficient mice exhibit decreased OB differentiation capacity. However, it has also been reported that IFN-γ and TNF-α synergistically promote OB apoptosis by inducing nitric oxide production or mitochondrial cytochrome c release, downregulating B cell lymphoma 2 expression and activating caspases. IFN-α inhibits OB progenitor proliferation and differentiation by inhibiting ALP activity and downregulating BMP-2 expression. Moreover, IFN-β exerts inhibitory effects on matrix mineralization by reducing the expression of COL1A1, fibronectin, fibulin, fibrillin, and laminin. Moreover, it has been recently reported that DEF6, also known as IFN regulatory factor 4-binding protein, suppresses osteoblastogenesis via endogenous type 1 IFN-mediated feedback inhibition. Taken together, these findings indicate that IFN-γ is an osteoblastogenic cytokine, although some exceptions may exist, while IFN-α/β is a potential anti-osteoblastogenic cytokine.

6. Concluding Remarks

Over the decades, the field of osteoimmunology has advanced to demonstrate the vital role played by cytokines in osteoblastogenesis and osteoclastogenesis and elucidate the potential use of such cytokines in clinical therapeutics. In particular, osteoblastogenic and anti-osteoblastogenic cytokines play an important role in osteoblastogenesis by linking the skeletal and immune systems. Dysregulation of osteoblastogenic and anti-osteoblastogenic cytokines can have a deleterious effect on bone metabolism homoeostasis. TNF-α, TNF-β, IL-1α, IL-4, IL-7, IL-12, IL-13, IL-23, IFN-α, IFN-β, LIF, CLC, and CNTF act as potent inhibitors of osteoblastogenesis, whereas IL-10, IL-11, IL-18, IFN-γ, CT-1, and OSM are osteoblastogenic (Table 1). Though each cytokine is supposed to have either stimulatory or inhibitory properties in osteoblastogenesis, the physiological mechanisms of action are complicated and possibly dependent on developmental stage, pathophysiological status, cytokine level, and the nature of the target cells.

References 153

  1. 1.

    Berendsen A.D., Olsen B.R. Bone development. Bone. 2015;80:14-18.

    Not in our library10.1016/j.bone.2015.04.035

  2. 2.

    Amarasekara D.S., Yun H., Kim S., Lee N., Kim H., Rho J. Regulation of Osteoclast Differentiation by Cytokine Networks. Immune Netw. 2018;18:e8.

    Not in our library10.4110/in.2018.18.e8

  3. 3.
    Bone Loss Triggered by the Cytokine Network in Inflammatory Autoimmune Diseases · 2015
    No notice
  4. 4.

    Huang W., Yang S., Shao J., Li Y.-P. Signaling and transcriptional regulation in osteoblast commitment and differentiation. Front. Biosci. A J. Virtual Libr. 2007;12:3068-3092.

    Not in our library10.2741/2296

  5. 5.

    Qiu Z.-Y., Cui Y., Wang X.-M., Wang X.-M., Qiu Z.-Y., Cui H. Natural bone tissue and its biomimetic. Mineralized Collagen Bone Graft Substitutes. 2019;1-22.

    Not in our library

  6. 6.

    Feldman D., Pike J.W., Glorieux F.H. Vitamin D. 2005;1845-1892.

    Not in our library

  7. 7.

    Stein G.S., Lian J.B. Molecular Mechanisms Mediating Proliferation/Differentiation Interrelationships during Progressive Development of the Osteoblast Phenotype. Endocr. Rev. 1993;14:424-442.

    Not in our library10.1210/edrv-14-4-424

  8. 8.

    Rutkovskiy A., Stensløkken K.-O., Vaage I.J. Osteoblast Differentiation at a Glance. Med. Sci. Monit. Basic Res. 2016;22:95-106.

    Not in our library10.12659/msmbr.901142

  9. 9.

    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

  10. 10.
    The Bone Extracellular Matrix in Bone Formation and Regeneration · 2020
    No notice
  11. 11.

    Cremers S., Garnero P., Seibel M.J., Bilezikian J.P., Raisz L.G., Martin T.J. Biochemical Markers of Bone Metabolism. Principles of Bone Biology. 2008;1857-1881.

    Not in our library

  12. 12.

    Boyce B.F., Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch. Biochem. Biophys. 2008;473:139-146.

    Not in our library10.1016/j.abb.2008.03.018

  13. 13.

    Horowitz M.C., Lorenzo J.A., Bilezikian J.P., Raisz L.G., Martin T.J. Local Regulators of Bone: IL-1, TNF, Lymphotoxin, Interferon-γ, the LIF/IL-6 Family, and Additional Cytokines. Principles of Bone Biology. 2008;1209-1234.

    Not in our library

  14. 14.

    Karsenty G., Bilezikian J.P., Martin T.J., Clemens T.L., Rosen C.J. Transcriptional control of osteoblast differentiation and function. Principles of Bone Biology. 2020;163-176.

    Not in our library

  15. 15.

    Komori T. Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res. 2009;339:189.

    Not in our library10.1007/s00441-009-0832-8

  16. 16.

    Schroeder T.M., Jensen E.D., Westendorf J.J. Runx2: A master organizer of gene transcription in developing and maturing osteoblasts. Birth Defects Res. C Embryo Today. 2005;75:213-225.

    Not in our library10.1002/bdrc.20043

  17. 17.

    Lee K.S., Kim H.J., Li Q.L., Chi X.Z., Ueta C., Komori T., Wozney J.M., Kim E.G., Choi J.Y., Ryoo H.M., et al. Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol. Cell Biol. 2000;20:8783-8792.

    Not in our library10.1128/mcb.20.23.8783-8792.2000

  18. 18.

    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

  19. 19.

    Narayanan A., Srinaath N., Rohini M., Selvamurugan N. Regulation of Runx2 by MicroRNAs in osteoblast differentiation. Life Sci. 2019;232:116676.

    Not in our library10.1016/j.lfs.2019.116676

  20. 20.

    Maruyama Z., Yoshida C.A., Furuichi T., Amizuka N., Ito M., Fukuyama R., Miyazaki T., Kitaura H., Nakamura K., Fujita T., et al. Runx2 determines bone maturity and turnover rate in postnatal bone development and is involved in bone loss in estrogen deficiency. Dev. Dyn. 2007;236:1876-1890.

    Not in our library10.1002/dvdy.21187

  21. 21.

    Qin X., Jiang Q., Miyazaki T., Komori T. Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells. Hum. Mol. Genet. 2019;28:896-911.

    Not in our library10.1093/hmg/ddy386

  22. 22.

    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

  23. 23.
    Recent Advances of Osterix Transcription Factor in Osteoblast Differentiation and Bone Formation · 2020
    No notice
  24. 24.

    Renn J., Winkler C. Osterix-mCherry transgenic medaka for in vivo imaging of bone formation. Dev. Dyn. 2009;238:241-248.

    Not in our library10.1002/dvdy.21836

  25. 25.
    Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation by regulating Fgfr2 and Fgfr3 · 2018
    No notice
  26. 26.

    Yang S., Hu L., Wang C., Wei F. PERK-eIF2α-ATF4 signaling contributes to osteogenic differentiation of periodontal ligament stem cells. J. Mol. Histol. 2020;51:125-135.

    Not in our library10.1007/s10735-020-09863-y

  27. 27.

    Yang X., Karsenty G. ATF4, the osteoblast accumulation of which is determined post-translationally, can induce osteoblast-specific gene expression in non-osteoblastic cells. J. Biol. Chem. 2004;279:47109-47114.

    Not in our library10.1074/jbc.m410010200

  28. 28.

    Xiao G., Jiang D., Ge C., Zhao Z., Lai Y., Boules H., Phimphilai M., Yang X., Karsenty G., Franceschi R.T. Cooperative interactions between activating transcription factor 4 and Runx2/Cbfa1 stimulate osteoblast-specific osteocalcin gene expression. J. Biol. Chem. 2005;280:30689-30696.

    Not in our library10.1074/jbc.m500750200

  29. 29.

    Yu S., Zhu K., Lai Y., Zhao Z., Fan J., Im H.-J., Chen D., Xiao G. atf4 promotes β-catenin expression and osteoblastic differentiation of bone marrow mesenchymal stem cells. Int. J. Biol. Sci. 2013;9:256-266.

    Not in our library10.7150/ijbs.5898

  30. 30.

    Tang J., Xie J., Chen W., Tang C., Wu J., Wang Y., Zhou X.-D., Zhou H.-D., Li Y.-P. Runt-related transcription factor 1 is required for murine osteoblast differentiation and bone formation. J. Biol. Chem. 2020;295:11669-11681.

    Not in our library10.1074/jbc.ra119.007896

  31. 31.

    Tang C.-Y., Chen W., Luo Y., Wu J., Zhang Y., McVicar A., McConnell M., Liu Y., Zhou H.-D., Li Y.-P. Runx1 up-regulates chondrocyte to osteoblast lineage commitment and promotes bone formation by enhancing both chondrogenesis and osteogenesis. Biochem. J. 2020;477:2421-2438.

    Not in our library10.1042/bcj20200036

  32. 32.

    Tang C.-Y., Wu M., Zhao D., Edwards D., McVicar A., Luo Y., Zhu G., Wang Y., Zhou H.-D., Chen W., et al. Runx1 is a central regulator of osteogenesis for bone homeostasis by orchestrating BMP and WNT signaling pathways. PLoS Genet. 2021;17:e1009233.

    Not in our library10.1371/journal.pgen.1009233

  33. 33.

    Wagner E.F., Eferl R. Fos/AP-1 proteins in bone and the immune system. Immunol. Rev. 2005;208:126-140.

    Not in our library10.1111/j.0105-2896.2005.00332.x

  34. 34.

    Kawamata A., Izu Y., Yokoyama H., Amagasa T., Wagner E.F., Nakashima K., Ezura Y., Hayata T., Noda M. JunD suppresses bone formation and contributes to low bone mass induced by estrogen depletion. J. Cell Biochem. 2008;103:1037-1045.

    Not in our library10.1002/jcb.21660

  35. 35.

    Dobreva G., Chahrour M., Dautzenberg M., Chirivella L., Kanzler B., Fariñas I., Karsenty G., Grosschedl R. SATB2 Is a Multifunctional Determinant of Craniofacial Patterning and Osteoblast Differentiation. Cell. 2006;125:971-986.

    Not in our library10.1016/j.cell.2006.05.012

  36. 36.

    Karsenty G., Wagner E.F. Reaching a genetic and molecular understanding of skeletal development. Dev. Cell. 2002;2:389-406.

    Not in our library10.1016/s1534-5807(02)00157-0

  37. 37.

    Bozec A., Bakiri L., Jimenez M., Schinke T., Amling M., Wagner E.F. Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production. J. Cell Biol. 2010;190:1093-1106.

    Not in our library10.1083/jcb.201002111

  38. 38.

    Zhang J., Tu Q., Grosschedl R., Kim M.S., Griffin T., Drissi H., Yang P., Chen J. Roles of SATB2 in osteogenic differentiation and bone regeneration. Tissue Eng. Part A. 2011;17:1767-1776.

    Not in our library10.1089/ten.tea.2010.0503

  39. 39.

    Dowrey T., Schwager E.E., Duong J., Merkuri F., Zarate Y.A., Fish J.L. Satb2 regulates proliferation and nuclear integrity of pre-osteoblasts. Bone. 2019;127:488-498.

    Not in our library10.1016/j.bone.2019.07.017

  40. 40.

    Hojo H., Ohba S., Chung U.-I. Signaling pathways regulating the specification and differentiation of the osteoblast lineage. Regen. Ther. 2015;1:57-62.

    Not in our library10.1016/j.reth.2014.10.002

  41. 41.

    Komiya Y., Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4:68-75.

    Not in our library10.4161/org.4.2.5851

  42. 42.
    Wnt Pathway in Bone Repair and Regeneration – What Do We Know So Far · 2019
    No notice
  43. 43.

    Latres E., Chiaur D.S., Pagano M. The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin. Oncogene. 1999;18:849-854.

    Not in our library10.1038/sj.onc.1202653

  44. 44.

    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

  45. 45.

    Takada I., Mihara M., Suzawa M., Ohtake F., Kobayashi S., Igarashi M., Youn M.Y., Takeyama K., Nakamura T., Mezaki Y., et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat. Cell Biol. 2007;9:1273-1285.

    Not in our library10.1038/ncb1647

  46. 46.

    Baksh D., Tuan R.S. Canonical and non-canonical wnts differentially affect the development potential of primary isolate of human bone marrow mesenchymal stem cells. J. Cell. Physiol. 2007;212:817-826.

    Not in our library10.1002/jcp.21080

  47. 47.

    Zayzafoon M. Calcium/calmodulin signaling controls osteoblast growth and differentiation. J. Cell Biochem. 2006;97:56-70.

    Not in our library10.1002/jcb.20675

  48. 48.

    Yamaguchi A., Komori T., Suda T. Regulation of Osteoblast Differentiation Mediated by Bone Morphogenetic Proteins, Hedgehogs, and Cbfa1. Endocr. Rev. 2000;21:393-411.

    Not in our library10.1210/edrv.21.4.0403

  49. 49.

    Reddi A.H. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat. Biotechnol. 1998;16:247-252.

    Not in our library10.1038/nbt0398-247

  50. 50.

    Ogasawara T., Kawaguchi H., Jinno S., Hoshi K., Itaka K., Takato T., Nakamura K., Okayama H. Bone morphogenetic protein 2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6. Mol. Cell. Biol. 2004;24:6560-6568.

    Not in our library10.1128/mcb.24.15.6560-6568.2004

  51. 51.

    Phimphilai M., Zhao Z., Boules H., Roca H., Franceschi R.T. BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2006;21:637-646.

    Not in our library10.1359/jbmr.060109

  52. 52.

    Lee M.H., Kwon T.G., Park H.S., Wozney J.M., Ryoo H.M. BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2. Biochem. Biophys. Res. Commun. 2003;309:689-694.

    Not in our library10.1016/j.bbrc.2003.08.058

  53. 53.

    Holleville N., Matéos S., Bontoux M., Bollerot K., Monsoro-Burq A.H. Dlx5 drives Runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. Dev. Biol. 2007;304:860-874.

    Not in our library10.1016/j.ydbio.2007.01.003

  54. 54.

    Erlebacher A., Filvaroff E.H., Ye J.-Q., Derynck R. Osteoblastic Responses to TGF-β during Bone Remodeling. Mol. Biol. Cell. 1998;9:1903-1918.

    Not in our library10.1091/mbc.9.7.1903

  55. 55.

    Kassem M., Kveiborg M., Eriksen E.F. Production and action of transforming growth factor-beta in human osteoblast cultures: Dependence on cell differentiation and modulation by calcitriol. Eur. J. Clin. Investig. 2000;30:429-437.

    Not in our library10.1046/j.1365-2362.2000.00645.x

  56. 56.

    Jilka R.L., Weinstein R.S., Bellido T., Parfitt A.M., Manolagas S.C. Osteoblast programmed cell death (apoptosis): Modulation by growth factors and cytokines. J. Bone Miner. Res. 1998;13:793-802.

    Not in our library10.1359/jbmr.1998.13.5.793

  57. 57.

    Lucas P.A. Chemotactic response of osteoblast-like cells to transforming growth factor beta. Bone. 1989;10:459-463.

    Not in our library10.1016/8756-3282(89)90079-3

  58. 58.

    Alliston T., Choy L., Ducy P., Karsenty G., Derynck R. TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J. 2001;20:2254-2272.

    Not in our library10.1093/emboj/20.9.2254

  59. 59.

    Chen G., Deng C., Li Y.-P. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int. J. Biol. Sci. 2012;8:272-288.

    Not in our library10.7150/ijbs.2929

  60. 60.

    Marie P.J., Miraoui H., Sévère N. FGF/FGFR signaling in bone formation: Progress and perspectives. Growth Factors. 2012;30:117-123.

    Not in our library10.3109/08977194.2012.656761

  61. 61.

    Liu Z., Xu J., Colvin J.S., Ornitz D.M. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev. 2002;16:859-869.

    Not in our library10.1101/gad.965602

  62. 62.

    Montero A., Okada Y., Tomita M., Ito M., Tsurukami H., Nakamura T., Doetschman T., Coffin J.D., Hurley M.M. Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. J. Clin. Investig. 2000;105:1085-1093.

    Not in our library10.1172/jci8641

  63. 63.

    Ohbayashi N., Shibayama M., Kurotaki Y., Imanishi M., Fujimori T., Itoh N., Takada S. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 2002;16:870-879.

    Not in our library10.1101/gad.965702

  64. 64.

    Yu K., Xu J., Liu Z., Sosic D., Shao J., Olson E.N., Towler D.A., Ornitz D.M. Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development. 2003;130:3063-3074.

    Not in our library10.1242/dev.00491

  65. 65.

    Bhattarai H.K., Shrestha S., Rokka K., Shakya R. Vitamin D, Calcium, Parathyroid Hormone, and Sex Steroids in Bone Health and Effects of Aging. J. Osteoporos. 2020;2020:9324505.

    Not in our library10.1155/2020/9324505

  66. 66.

    Baron R., Hesse E. Update on bone anabolics in osteoporosis treatment: Rationale, current status, and perspectives. J. Clin. Endocrinol. Metab. 2012;97:311-325.

    Not in our library10.1210/jc.2011-2332

  67. 67.

    Tyson D.R., Swarthout J.T., Partridge N.C. Increased osteoblastic c-fos expression by parathyroid hormone requires protein kinase A phosphorylation of the cyclic adenosine 3’,5’-monophosphate response element-binding protein at serine 133. Endocrinology. 1999;140:1255-1261.

    Not in our library10.1210/endo.140.3.6567

  68. 68.

    Zhang R., Edwards J.R., Ko S.Y., Dong S., Liu H., Oyajobi B.O., Papasian C., Deng H.W., Zhao M. Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts. PLoS ONE. 2011;6:e20780.

    Not in our library10.1371/journal.pone.0020780

  69. 69.

    Huang W.C., Xie Z., Konaka H., Sodek J., Zhau H.E., Chung L.W. Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: Role of cAMP-dependent protein kinase A signaling pathway. Cancer Res. 2005;65:2303-2313.

    Not in our library10.1158/0008-5472.can-04-3448

  70. 70.

    Qiu T., Xian L., Crane J., Wen C., Hilton M., Lu W., Newman P., Cao X. PTH receptor signaling in osteoblasts regulates endochondral vascularization in maintenance of postnatal growth plate. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2015;30:309-317.

    Not in our library10.1002/jbmr.2327

  71. 71.

    Yang J., Andre P., Ye L., Yang Y.-Z. The Hedgehog signalling pathway in bone formation. Int. J. Oral Sci. 2015;7:73-79.

    Not in our library10.1038/ijos.2015.14

  72. 72.

    AlMuraikhi N., Almasoud N., Binhamdan S., Younis G., Ali D., Manikandan M., Vishnubalaji R., Atteya M., Siyal A., Alfayez M., et al. Hedgehog Signaling Inhibition by Smoothened Antagonist BMS-833923 Reduces Osteoblast Differentiation and Ectopic Bone Formation of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells Int. 2019;2019:3435901.

    Not in our library10.1155/2019/3435901

  73. 73.

    Wu F., Zhang Y., Sun B., McMahon A.P., Wang Y. Hedgehog Signaling: From Basic Biology to Cancer Therapy. Cell Chem. Biol. 2017;24:252-280.

    Not in our library10.1016/j.chembiol.2017.02.010

  74. 74.

    Cai J.Q., Huang Y.Z., Chen X.H., Xie H.L., Zhu H.M., Tang L., Yang Z.M., Huang Y.C., Deng L. Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell Biol. Int. 2012;36:349-355.

    Not in our library10.1042/cbi20110284

  75. 75.

    Long F., Chung U.I., Ohba S., McMahon J., Kronenberg H.M., McMahon A.P. Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development. 2004;131:1309-1318.

    Not in our library10.1242/dev.01006

  76. 76.

    Zheng M.H., Wood D.J., Papadimitriou J.M. What’s new in the role of cytokines on osteoblast proliferation and differentiation? Pathol. Res. Pract. 1992;188:1104-1121.

    Not in our library10.1016/s0344-0338(11)81263-x

  77. 77.

    Chen E., Liu G., Zhou X., Zhang W., Wang C., Hu D., Xue D., Pan Z. Concentration-dependent, dual roles of IL-10 in the osteogenesis of human BMSCs via P38/MAPK and NF-kappaB signaling pathways. FASEB J. 2018;32:4917-4929.

    Not in our library10.1096/fj.201701256rrr

  78. 78.

    Dresner-Pollak R., Gelb N., Rachmilewitz D., Karmeli F., Weinreb M. Interleukin 10-deficient mice develop osteopenia, decreased bone formation, and mechanical fragility of long bones. Gastroenterology. 2004;127:792-801.

    Not in our library10.1053/j.gastro.2004.06.013

  79. 79.

    Matsumoto T., Kuriwaka-Kido R., Kondo T., Endo I., Kido S. Regulation of osteoblast differentiation by interleukin-11 via AP-1 and Smad signaling. Endocr. J. 2012;59:91-101.

    Not in our library10.1507/endocrj.ej11-0219

  80. 80.

    Suga K., Saitoh M., Fukushima S., Takahashi K., Nara H., Yasuda S., Miyata K. Interleukin-11 induces osteoblast differentiation and acts synergistically with bone morphogenetic protein-2 in C3H10T1/2 cells. J. Interferon Cytokine Res. 2001;21:695-707.

    Not in our library10.1089/107999001753124435

  81. 81.

    Suga K., Saitoh M., Kokubo S., Fukushima S., Kaku S., Yasuda S., Miyata K. Interleukin-11 acts synergistically with bone morphogenetic protein-2 to accelerate bone formation in a rat ectopic model. J. Interferon Cytokine Res. 2003;23:203-207.

    Not in our library10.1089/107999003765027401

  82. 82.

    Cornish J., Gillespie M.T., Callon K.E., Horwood N.J., Moseley J.M., Reid I.R. Interleukin-18 Is a Novel Mitogen of Osteogenic and Chondrogenic Cells. Endocrinology. 2003;144:1194-1201.

    Not in our library10.1210/en.2002-220936

  83. 83.

    Gowen M., MacDonald B.R., Russell R.G. Actions of recombinant human gamma-interferon and tumor necrosis factor alpha on the proliferation and osteoblastic characteristics of human trabecular bone cells in vitro. Arthritis Rheum. 1988;31:1500-1507.

    Not in our library10.1002/art.1780311206

  84. 84.

    Maruhashi T., Kaifu T., Yabe R., Seno A., Chung S.H., Fujikado N., Iwakura Y. DCIR maintains bone homeostasis by regulating IFN-gamma production in T cells. J. Immunol. 2015;194:5681-5691.

    Not in our library10.4049/jimmunol.1500273

  85. 85.

    Vidal C., Bermeo S., Li W., Huang D., Kremer R., Duque G. Interferon gamma inhibits adipogenesis in vitro and prevents marrow fat infiltration in oophorectomized mice. Stem Cells. 2012;30:1042-1048.

    Not in our library10.1002/stem.1063

  86. 86.

    Duque G., Huang D.C., Dion N., Macoritto M., Rivas D., Li W., Yang X.F., Li J., Lian J., Marino F.T., et al. Interferon-gamma plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice. J. Bone Miner. Res. 2011;26:1472-1483.

    Not in our library10.1002/jbmr.350

  87. 87.

    Duque G., Huang D.C., Macoritto M., Rivas D., Yang X.F., Ste-Marie L.G., Kremer R. Autocrine regulation of interferon gamma in mesenchymal stem cells plays a role in early osteoblastogenesis. Stem Cells. 2009;27:550-558.

    Not in our library10.1634/stemcells.2008-0886

  88. 88.

    Sims N.A., Quinn J.M.W. Osteoimmunology: Oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease. Bonekey Rep. 2014;3:527.

    Not in our library10.1038/bonekey.2014.22

  89. 89.

    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

  90. 90.

    Quach J.M., Walker E.C., Allan E., Solano M., Yokoyama A., Kato S., Sims N.A., Gillespie M.T., Martin T.J. Zinc finger protein 467 is a novel regulator of osteoblast and adipocyte commitment. J. Biol. Chem. 2011;286:4186-4198.

    Not in our library10.1074/jbc.m110.178251

  91. 91.

    Gilbert L., He X., Farmer P., Boden S., Kozlowski M., Rubin J., Nanes M.S. Inhibition of Osteoblast Differentiation by Tumor Necrosis Factor-α. Endocrinology. 2000;141:3956-3964.

    Not in our library10.1210/endo.141.11.7739

  92. 92.

    Gilbert L., He X., Farmer P., Rubin J., Drissi H., van Wijnen A.J., Lian J.B., Stein G.S., Nanes M.S. Expression of the Osteoblast Differentiation Factor RUNX2 (Cbfa1/AML3/Pebp2αA) Is Inhibited by Tumor Necrosis Factor-α. J. Biol. Chem. 2002;277:2695-2701.

    Not in our library10.1074/jbc.m106339200

  93. 93.

    Abbas S., Zhang Y.H., Clohisy J.C., Abu-Amer Y. Tumor necrosis factor-alpha inhibits pre-osteoblast differentiation through its type-1 receptor. Cytokine. 2003;22:33-41.

    Not in our library10.1016/s1043-4666(03)00106-6

  94. 94.

    Mukai T., Otsuka F., Otani H., Yamashita M., Takasugi K., Inagaki K., Yamamura M., Makino H. TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling. Biochem. Biophys. Res. Commun. 2007;356:1004-1010.

    Not in our library10.1016/j.bbrc.2007.03.099

  95. 95.

    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

  96. 96.

    Zhao L., Huang J., Zhang H., Wang Y., Matesic L.E., Takahata M., Awad H., Chen D., Xing L. Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1. Stem Cells. 2011;29:1601-1610.

    Not in our library10.1002/stem.703

  97. 97.

    Zuo C., Zhao X., Shi Y., Wu W., Zhang N., Xu J., Wang C., Hu G., Zhang X. TNF-α inhibits SATB2 expression and osteoblast differentiation through NF-κB and MAPK pathways. Oncotarget. 2017;9:4833-4850.

    Not in our library10.18632/oncotarget.23373

  98. 98.

    Du D., Zhou Z., Zhu L., Hu X., Lu J., Shi C., Chen F., Chen A. TNF-α suppresses osteogenic differentiation of MSCs by accelerating P2Y2 receptor in estrogen-deficiency induced osteoporosis. Bone. 2018;117:161-170.

    Not in our library10.1016/j.bone.2018.09.012

  99. 99.

    Constanze B., Popper B., Aggarwal B.B., Shakibaei M. Evidence that TNF-β suppresses osteoblast differentiation of mesenchymal stem cells and resveratrol reverses it through modulation of NF-κB, Sirt1 and Runx2. Cell Tissue Res. 2020;381:83-98.

    Not in our library10.1007/s00441-020-03188-8

  100. 100.

    Guo C., Yang X.-G., Wang F., Ma X.-Y. IL-1α induces apoptosis and inhibits the osteoblast differentiation of MC3T3-E1 cells through the JNK and p38 MAPK pathways. Int. J. Mol. Med. 2016;38:319-327.

    Not in our library10.3892/ijmm.2016.2606

  101. 101.

    Ura K., Morimoto I., Watanabe K., Saito K., Yanagihara N., Eto S. Interleukin (IL)-4 and IL-13 Inhibit the Differentiation of Murine Osteoblastic MC3T3-E1 Cells. Endocr. J. 2000;47:293-302.

    Not in our library10.1507/endocrj.47.293

  102. 102.

    Frost A., Jonsson K.B., Brandstrom H., Ljunghall S., Nilsson O., Ljunggren O. Interleukin (IL)-13 and IL-4 inhibit proliferation and stimulate IL-6 formation in human osteoblasts: Evidence for involvement of receptor subunits IL-13R, IL-13Ralpha, and IL-4Ralpha. Bone. 2001;28:268-274.

    Not in our library10.1016/s8756-3282(00)00449-x

  103. 103.

    Silfverswärd C.-J., Frost A., Brändström H., Nilsson O., Ljunggren Ö. Interleukin-4 and interleukin-13 potentiate interleukin-1 induced secretion of interleukin-6 in human osteoblast-like cells. J. Orthop. Res. 2004;22:1058-1062.

    Not in our library10.1016/j.orthres.2004.02.008

  104. 104.

    Riancho J.A., González-Marcías J., Amado J.A., Olmos J.M., Fernández-Luna J.L. Interleukin-4 as a bone regulatory factor: Effects on murine osteoblast-like cells. J. Endocrinol. Investig. 1995;18:174-179.

    Not in our library10.1007/bf03347799

  105. 105.

    Weitzmann M.N., Roggia C., Toraldo G., Weitzmann L., Pacifici R. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J. Clin. Investig. 2002;110:1643-1650.

    Not in our library10.1172/jci0215687

  106. 106.

    Jian C.-X., Fan Q.-S., Hu Y.-H., He Y., Li M.-Z., Zheng W.-Y., Ren Y., Li C.-J. IL-7 suppresses osteogenic differentiation of periodontal ligament stem cells through inactivation of mitogen-activated protein kinase pathway. Organogenesis. 2016;12:183-193.

    Not in our library10.1080/15476278.2016.1229726

  107. 107.

    Giuliani N., Colla S., Morandi F., Lazzaretti M., Sala R., Bonomini S., Grano M., Colucci S., Svaldi M., Rizzoli V. Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. Blood. 2005;106:2472-2483.

    Not in our library10.1182/blood-2004-12-4986

  108. 108.

    Xu J., Wang Y., Li J., Zhang X., Geng Y., Huang Y., Dai K., Zhang X. IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4(+) T cells. Cell Death Differ. 2016;23:1941-1951.

    Not in our library10.1038/cdd.2016.72

  109. 109.

    Xu J., Li J., Hu Y., Dai K., Gan Y., Zhao J., Huang M., Zhang X. IL-23, but not IL-12, plays a critical role in inflammation-mediated bone disorders. Theranostics. 2020;10:3925-3938.

    Not in our library10.7150/thno.41378

  110. 110.

    Malaval L., Aubin J.E. Biphasic effects of leukemia inhibitory factor on osteoblastic differentiation. J. Cell Biochem. 2001;81(Suppl. S36):63-70.

    Not in our library10.1002/jcb.1086

  111. 111.

    Matsushita K., Itoh S., Ikeda S., Yamamoto Y., Yamauchi Y., Hayashi M. LIF/STAT3/SOCS3 signaling pathway in murine bone marrow stromal cells suppresses osteoblast differentiation. J. Cell Biochem. 2014;115:1262-1268.

    Not in our library10.1002/jcb.24777

  112. 112.

    Wang T., Yan R.Q., Xu X.Y., Cao L.L., Liu J.Y., Zheng M.R., Li W.D. Effects of Leukaemia Inhibitory Factor Receptor on the Early Stage of Osteogenic Differentiation of Human Bone Marrow Mesenchymal Cells. Folia Biol. 2018;64:186-194.

    Not in our library10.14712/fb2018064050186

  113. 113.

    Nahlé S., Pasquin S., Laplante V., Rousseau F., Sharma M., Gauchat J.F. Cardiotrophin-like cytokine (CLCF1) modulates mesenchymal stem cell osteoblastic differentiation. J. Biol. Chem. 2019;294:11952-11959.

    Not in our library10.1074/jbc.ac119.008361

  114. 114.

    McGregor N.E., Poulton I.J., Walker E.C., Pompolo S., Quinn J.M.W., Martin T.J., Sims N.A. Ciliary Neurotrophic Factor Inhibits Bone Formation and Plays a Sex-Specific Role in Bone Growth and Remodeling. Calcif. Tissue Int. 2010;86:261-270.

    Not in our library10.1007/s00223-010-9337-4

  115. 115.

    Johnson R.W., White J.D., Walker E.C., Martin T.J., Sims N.A. Myokines (muscle-derived cytokines and chemokines) including ciliary neurotrophic factor (CNTF) inhibit osteoblast differentiation. Bone. 2014;64:47-56.

    Not in our library10.1016/j.bone.2014.03.053

  116. 116.

    Oreffo R.O., Romberg S., Virdi A.S., Joyner C.J., Berven S., Triffitt J.T. Effects of interferon alpha on human osteoprogenitor cell growth and differentiation in vitro. J. Cell Biochem. 1999;74:372-385.

    Not in our library10.1002/(sici)1097-4644(19990901)74:3<372::aid-jcb6>3.0.co;2-h

  117. 117.

    Woeckel V.J., Eijken M., van de Peppel J., Chiba H., van der Eerden B.C., van Leeuwen J.P. IFNβ impairs extracellular matrix formation leading to inhibition of mineralization by effects in the early stage of human osteoblast differentiation. J. Cell Physiol. 2012;227:2668-2676.

    Not in our library10.1002/jcp.23009

  118. 118.

    Deng Z., Ng C., Inoue K., Chen Z., Xia Y., Hu X., Greenblatt M., Pernis A., Zhao B. Def6 regulates endogenous type-I interferon responses in osteoblasts and suppresses osteogenesis. eLife. 2020;9:e59659.

    Not in our library10.7554/elife.59659

  119. 119.

    Sonomoto K., Yamaoka K., Oshita K., Fukuyo S., Zhang X., Nakano K., Okada Y., Tanaka Y. Interleukin-1β induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt-5a/receptor tyrosine kinase-like orphan receptor 2 pathway. Arthritis Rheum. 2012;64:3355-3363.

    Not in our library10.1002/art.34555

  120. 120.

    Stashenko P., Dewhirst F.E., Rooney M.L., Desjardins L.A., Heeley J.D. Interleukin-1 beta is a potent inhibitor of bone formation in vitro. J. Bone Miner. Res. 1987;2:559-565.

    Not in our library10.1002/jbmr.5650020612

  121. 121.

    Lacey D.C., Simmons P.J., Graves S.E., Hamilton J.A. Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: Implications for bone repair during inflammation. Osteoarthr. Cartil. 2009;17:735-742.

    Not in our library10.1016/j.joca.2008.11.011

  122. 122.

    Barhanpurkar A.P., Gupta N., Srivastava R.K., Tomar G.B., Naik S.P., Joshi S.R., Pote S.T., Mishra G.C., Wani M.R. IL-3 promotes osteoblast differentiation and bone formation in human mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2012;418:669-675.

    Not in our library10.1016/j.bbrc.2012.01.074

  123. 123.

    Ehrlich L.A., Chung H.Y., Ghobrial I., Choi S.J., Morandi F., Colla S., Rizzoli V., Roodman G.D., Giuliani N. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood. 2005;106:1407-1414.

    Not in our library10.1182/blood-2005-03-1080

  124. 124.

    Kaneshiro S., Ebina K., Shi K., Higuchi C., Hirao M., Okamoto M., Koizumi K., Morimoto T., Yoshikawa H., Hashimoto J. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. J. Bone Miner. Metab. 2014;32:378-392.

    Not in our library10.1007/s00774-013-0514-1

  125. 125.

    Malysheva K., de Rooij K., Lowik C.W., Baeten D.L., Rose-John S., Stoika R., Korchynskyi O. Interleukin 6/Wnt interactions in rheumatoid arthritis: Interleukin 6 inhibits Wnt signaling in synovial fibroblasts and osteoblasts. Croat. Med. J. 2016;57:89-98.

    Not in our library10.3325/cmj.2016.57.89

  126. 126.

    Iwasaki K., Komaki M., Mimori K., Leon E., Izumi Y., Ishikawa I. IL-6 induces osteoblastic differentiation of periodontal ligament cells. J. Dent. Res. 2008;87:937-942.

    Not in our library10.1177/154405910808701002

  127. 127.

    Bastidas-Coral A.P., Bakker A.D., Zandieh-Doulabi B., Kleverlaan C.J., Bravenboer N., Forouzanfar T., Klein-Nulend J. Cytokines TNF-α, IL-6, IL-17F, and IL-4 Differentially Affect Osteogenic Differentiation of Human Adipose Stem Cells. Stem Cells Int. 2016;2016:1318256.

    Not in our library10.1155/2016/1318256

  128. 128.

    Fukuyo S., Yamaoka K., Sonomoto K., Oshita K., Okada Y., Saito K., Yoshida Y., Kanazawa T., Minami Y., Tanaka Y. IL-6-accelerated calcification by induction of ROR2 in human adipose tissue-derived mesenchymal stem cells is STAT3 dependent. Rheumatology. 2014;53:1282-1290.

    Not in our library10.1093/rheumatology/ket496

  129. 129.

    Takeda H., Kikuchi T., Soboku K., Okabe I., Mizutani H., Mitani A., Ishihara Y., Noguchi T. Effect of IL-15 and Natural Killer Cells on Osteoclasts and Osteoblasts in a Mouse Coculture. Inflammation. 2014;37:657-669.

    Not in our library10.1007/s10753-013-9782-0

  130. 130.

    Loro E., Ramaswamy G., Chandra A., Tseng W.-J., Mishra M.K., Shore E.M., Khurana T.S. IL15RA is required for osteoblast function and bone mineralization. Bone. 2017;103:20-30.

    Not in our library10.1016/j.bone.2017.06.003

  131. 131.
    T-Lymphocytes Enable Osteoblast Maturation via IL-17F during the Early Phase of Fracture Repair · 2012
    No notice
  132. 132.

    Croes M., Öner F.C., van Neerven D., Sabir E., Kruyt M.C., Blokhuis T.J., Dhert W.J.A., Alblas J. Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Bone. 2016;84:262-270.

    Not in our library10.1016/j.bone.2016.01.010

  133. 133.

    Croes M., Kruyt M.C., Groen W.M., van Dorenmalen K.M.A., Dhert W.J.A., Öner F.C., Alblas J. Interleukin 17 enhances bone morphogenetic protein-2-induced ectopic bone formation. Sci. Rep. 2018;8:7269.

    Not in our library10.1038/s41598-018-25564-9

  134. 134.

    Kim H.J., Seo S.J., Kim J.-Y., Kim Y.-G., Lee Y. IL-17 promotes osteoblast differentiation, bone regeneration, and remodeling in mice. Biochem. Biophys. Res. Commun. 2020;524:1044-1050.

    Not in our library10.1016/j.bbrc.2020.02.054

  135. 135.

    Liao C., Zhang C., Jin L., Yang Y. IL-17 alters the mesenchymal stem cell niche towards osteogenesis in cooperation with osteocytes. J. Cell. Physiol. 2020;235:4466-4480.

    Not in our library10.1002/jcp.29323

  136. 136.
    IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis · 2018
    No notice
  137. 137.

    Kenna T.J., Davidson S.I., Duan R., Bradbury L.A., McFarlane J., Smith M., Weedon H., Street S., Thomas R., Thomas G.P., et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive γ/δ T cells in patients with active ankylosing spondylitis. Arthritis Rheum. 2012;64:1420-1429.

    Not in our library10.1002/art.33507

  138. 138.

    Kim Y.G., Park J.W., Lee J.M., Suh J.Y., Lee J.K., Chang B.S., Um H.S., Kim J.Y., Lee Y. IL-17 inhibits osteoblast differentiation and bone regeneration in rat. Arch. Oral Biol. 2014;59:897-905.

    Not in our library10.1016/j.archoralbio.2014.05.009

  139. 139.

    Shaw A.T., Maeda Y., Gravallese E.M. IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis. Arthritis Res. Ther. 2016;18:104.

    Not in our library10.1186/s13075-016-0998-x

  140. 140.

    Zhang J.-R., Pang D.-D., Tong Q., Liu X., Su D.-F., Dai S.-M. Different Modulatory Effects of IL-17, IL-22, and IL-23 on Osteoblast Differentiation. Mediat. Inflamm. 2017;2017:5950395.

    Not in our library10.1155/2017/5950395

  141. 141.

    Ye C., Zhang W., Hang K., Chen M., Hou W., Chen J., Chen X., Chen E., Tang L., Lu J., et al. Extracellular IL-37 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the PI3K/AKT signaling pathway. Cell Death Dis. 2019;10:753.

    Not in our library10.1038/s41419-019-1904-7

  142. 142.

    Zeng Q., Song R., Fullerton D.A., Ao L., Zhai Y., Li S., Ballak D.B., Cleveland J.C., Reece T.B., McKinsey T.A., et al. Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice. Proc. Natl. Acad. Sci. USA. 2017;114:1631-1636.

    Not in our library10.1073/pnas.1619667114

  143. 143.

    O’Shea J.J., Gadina M., Siegel R., Rich R.R., Fleisher T.A., Shearer W.T., Schroeder H.W., Frew A.J., Weyand C.M. 9—Cytokines and cytokine receptors. Clinical Immunology. 2013;108-135.

    Not in our library

  144. 144.

    Rose-John S. Interleukin-6 Family Cytokines. Cold Spring Harb. Perspect. Biol. 2018;10.

    Not in our library10.1101/cshperspect.a028415

  145. 145.

    Srinivasan L., Harris M.C., Kilpatrick L.E., Polin R.A., Abman S.H., Rowitch D.H., Benitz W.E., Fox W.W. 128—Cytokines and Inflammatory Response in the Fetus and Neonate. Fetal and Neonatal Physiology. 2017;1241-1254.

    Not in our library

  146. 146.

    Kido S., Kuriwaka-Kido R., Imamura T., Ito Y., Inoue D., Matsumoto T. Mechanical stress induces Interleukin-11 expression to stimulate osteoblast differentiation. Bone. 2009;45:1125-1132.

    Not in our library10.1016/j.bone.2009.07.087

  147. 147.

    Kido S., Kuriwaka-Kido R., Umino-Miyatani Y., Endo I., Inoue D., Taniguchi H., Inoue Y., Imamura T., Matsumoto T. Mechanical stress activates Smad pathway through PKCδ to enhance interleukin-11 gene transcription in osteoblasts. PLoS ONE. 2010;5:e13090.

    Not in our library10.1371/journal.pone.0013090

  148. 148.

    Lorenzo J., Lorenzo J., Horowitz M.C., Choi Y., Takayanagi H., Schett G. The Effects of Immune Cell Products (Cytokines and Hematopoietic Cell Growth Factors) on Bone Cells. Osteoimmunology. 2016;143-167.

    Not in our library

  149. 149.

    Giri J.G., Kumaki S., Ahdieh M., Friend D.J., Loomis A., Shanebeck K., DuBose R., Cosman D., Park L.S., Anderson D.M. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J. 1995;14:3654-3663.

    Not in our library10.1002/j.1460-2075.1995.tb00035.x

  150. 150.

    Jin W., Dong C. IL-17 cytokines in immunity and inflammation. Emerg. Microbes Infect. 2013;2:e60.

    Not in our library10.1038/emi.2013.58

  151. 151.
    Interferon-Gamma-Mediated Osteoimmunology · 2018
    No notice
  152. 152.

    Iguchi M., Hiroi M., Kanegae H., Ohmori Y. Costimulation of Murine Osteoblasts with Interferon-γ and Tumor Necrosis Factor-α Induces Apoptosis through Downregulation of Bcl-2 and Release of Cytochrome c from Mitochondria. Mediat. Inflamm. 2018;2018:3979606.

    Not in our library10.1155/2018/3979606

  153. 153.

    Damoulis P.D., Hauschka P.V. Nitric Oxide Acts in Conjunction with Proinflammatory Cytokines to Promote Cell Death in Osteoblasts. J. Bone Miner. Res. 1997;12:412-422.

    Not in our library10.1359/jbmr.1997.12.3.412

Cited by papers we hold 3

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.