Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis

Hwang, Seung-Jun; Choi, Bok Kyoung; Kang, Suk-Yun; Chang, Jae-Ho; Kim, Yong‐Gil; Chung, Yeon‐Ho; Sohn, Dong Hyun; So, Min Wook; Lee, Chang‐Keun; Robinson, William H.; Chang, Eun‐Ju

doi:10.1186/ar3693

Cited by 126 publications

(117 citation statements)

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“…Recently, it was reported that IL-34 was expressed in synovial tissues obtained from rheumatoid arthritis patients, and tumor necrosis factor α (TNFα) stimulated IL-34 expression in those synovial fibroblasts in culture (33,34). Giant cell tumors of bone have been shown to express IL-34 (17).…”

Section: Discussionmentioning

confidence: 99%

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Nakamichi¹,

Mizoguchi²,

Arai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Osteoclasts are generated from monocyte/macrophage-lineage precursors in response to colony-stimulating factor 1 (CSF-1) and receptor activator of nuclear factor-κB ligand (RANKL). CSF-1-mutated CSF-1 op/op mice as well as RANKL −/− mice exhibit osteopetrosis (OP) caused by osteoclast deficiency. We previously identified RANKL receptor (RANK)/CSF-1 receptor (CSF-1R) double-positive cells as osteoclast precursors (OCPs), which existed in bone in RANKL −/− mice. Here we show that OCPs do not exist in bone but in spleen in CSF-1 op/op mice, and spleen acts as their reservoir. IL-34, a newly discovered CSF-1R ligand, was highly expressed in vascular endothelial cells in spleen in CSF-1 op/op mice. Vascular endothelial cells in bone also expressed IL-34, but its expression level was much lower than in spleen, suggesting a role of IL-34 in the splenic generation of OCPs. Splenectomy (SPX) blocked CSF-1-induced osteoclastogenesis in CSF-1 op/op mice. Osteoclasts appeared in aged CSF-1 op/op mice with up-regulation of IL-34 expression in spleen and bone. Splenectomy blocked the age-associated appearance of osteoclasts. The injection of 2-methylene-19-nor-(20S)-1α,25(OH) 2 D 3 (2MD), a potent analog of 1α,25-dihidroxyvitamin D 3 , into CSF-1 op/op mice induced both hypercalcemia and osteoclastogenesis. Administration of 2MD enhanced IL-34 expression not only in spleen but also in bone through a vitamin D receptor-mediated mechanism. Either splenectomy or siRNA-mediated knockdown of IL-34 suppressed 2MD-induced osteoclastogenesis. These results suggest that IL-34 plays a pivotal role in maintaining the splenic reservoir of OCPs, which are transferred to bone in response to diverse stimuli, in CSF-1 op/op mice. The present study also suggests that the IL-34 gene in vascular endothelial cells is a unique target of vitamin D. CSF-1 is the most potent growth factor for monocytes/macrophages (3), but its synthesis by osteoblasts occurs independently of PTH and 1α,25(OH) 2 D 3 (2). CSF-1 op/op mice cannot produce a functionally active CSF-1 (4), and therefore, exhibit monocytopenia and osteopetrosis (OP) (5, 6). However, several curious phenomena have been observed in CSF-1 op/op mice. First, osteoclasts are totally absent in young CSF-1 op/op mice, but appear in aged CSF-1 op/op mice (7). Second, osteopetrotic characteristics of CSF-1R −/− mice are more severe than those of CSF-1 op/op mice (8). Third, F4/80 + [F4/80(+)] macrophages exist in the splenic red pulp in CSF-1 op/op mice as well as in WT mice, and their number is regulated by a mechanism independently of CSF-1 (9, 10). Fourth, the administration of vascular endothelial growth factor (VEGF) rescues osteopetrosis in CSF-1 op/op mice (11, 12), but VEGF cannot substitute for CSF-1 to induce osteoclast formation in vitro (13).Recently, Lin et al. (14) discovered IL-34, as a new ligand for CSF-1R. The amino acid sequence of IL-34 was quite different from that of CSF-1, but IL-34 promoted macrophage colony formation like CSF-1 did. IL-34 was specifically expressed in splen...

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Section: Discussionmentioning

confidence: 99%

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Nakamichi¹,

Mizoguchi²,

Arai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…However, circulating CSF-1 (Stanley 1979;Janowska-Wieczorek et al 1991) shows humoral regulation (Cecchini et al 1994;Pollard and Stanley 1996;Dai et al 2004). In contrast, IL-34 is not detectable in the circulation of healthy individuals (Hwang et al 2012;Tian et al 2013) and thus IL-34 actions are likely to be restricted to the local microenvironments in which they are expressed. Through their different spatiotemporal expression, the two ligands play complementary roles in regulating the development, maintenance, and activity of specific macrophage populations, Langerhans cells, neuronal progenitors (Wei et al 2010;Greter et al 2012;Nandi et al 2012;Wang et al 2012), as well as osteoclasts (Dai et al 2002) and Paneth cells (Huynh et al 2009) and the regulation of cells of the female reproductive tract (Wei et al 2010).…”

Section: Csf-1r Expressionmentioning

confidence: 99%

CSF-1 Receptor Signaling in Myeloid Cells

Stanley

Chiţu

2014

Cold Spring Harbor Perspectives in Biology

596

521

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The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). It plays important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia. It also regulates the differentiation of neural progenitor cells and controls functions of oocytes and trophoblastic cells in the female reproductive tract. Owing to this broad tissue expression pattern, it plays a central role in neoplastic, inflammatory, and neurological diseases. In this review we summarize the evolution, structure, and regulation of expression of the CSF-1R gene. We discuss the structures of CSF-1, IL-34, and the CSF-1R and the mechanism of ligand binding to and activation of the receptor. We further describe the pathways regulating macrophage survival, proliferation, differentiation, and chemotaxis downstream from the CSF-1R.

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“…IL-6, induced by TNF-α, contributes to bone destruction by stimulating RANKL expression and by regulating development of Th17 lymphocytes [67]. TNF-α upregulates IL-34, which mediates chemotactic migration of OCPs and supports the RANKL-induced osteoclastogenesis in the absence of M-CSF [25].…”

Section: Effect Of Arthritic Mediators On Osteoclast Progenitorsmentioning

confidence: 99%

Section: Differentiation Of Osteoclastsmentioning

confidence: 99%

“…M-CSF induces the proliferation of OCPs, supports their survival and upregulates RANK expression [23,24]. IL-34, by binding to cFms, is able to replace M-CSF in RANKL-induced osteoclastogenesis [7,8,25].RANK lacks the intrinsic enzymatic activity in its intracellular domain and transduces signaling by recruiting adaptor molecules from the TRAF (TNF receptor-associated factor) family of proteins, mainly TRAF6 [23,24]. Upon RANK/TRAF6 complex formation, multiple signaling pathways are activated, including classical and alternative NF-κB pathways, protein tyrosine kinases (BtK/Tec), calcium signaling and mitogen-activated protein kinase (MAPK) pathways (p38 and Erk).…”

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confidence: 99%

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Induction of osteoclast progenitors in inflammatory conditions: key to bone destruction in arthritis

Šućur

Katavić

Kelava

et al. 2014

International Orthopaedics (SICOT)

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The inflammatory milieu favors recruitment and activation of osteoclasts, and leads to bone destruction as a serious complication associated with arthritis and with other inflammatory processes.The frequency and activity of osteoclast progenitors (OCPs) correspond to arthritis severity, and may be used to monitor disease progression and bone resorption, indicating the need for detailed characterization of the discrete OCP subpopulations. Collectively, current studies suggest that the most potent murine bone marrow OCP population can be identified among lymphoid negative population within the immature myeloid lineage cells, as B220 -CD3 -CD11b -/lo CD115 + CD117 + CX3CR1 + and possibly also Ter119 -CD11c -CD135 lo Ly6C + RANK -. In the peripheral blood OCP population bears the monocytoid phenotype B220 -CD3 -NK1.1 -CD11b + Ly-6C hi CD115 + CX3CR1 + , presumably expressing RANK in committed OCPs. Much less is known about human OCPs and their regulation in arthritis, but the circulating OCP subset is, most probably, comprised among the lymphoid negative population (CD3 -CD19 -CD56 -), within immature monocyte subset (CD11b + CD14 + CD16 -), expressing receptors for M-CSF and RANKL (CD115 + RANK + ). Our preliminary data confirmed positive association between the proportion of peripheral blood OCPs, defined as CD3 -CD19 -CD56 -CD11b + CD14 + , and the disease activity score (DAS28) in the follow-up samples from patient with psoriatic arthritis receiving anti-TNF therapy. In addition, we reviewed cytokines and chemokines which, directly or indirectly, activate OCPs and enhance their differentiation potential, thus mediating osteoresorption.Control of the activity and migratory behavior of OCPs as well as the identification of crucial bone/joint chemotactic mediators represent promising therapeutic targets in arthritis.Keyword: osteoclast progenitors, arthritis, inflammation, cytokines, chemokines, osteoresorption 3 Inflammation induced bone lossBone is a highly dynamic tissue important for its mechanical and metabolic functions, and characterized by rapid response to numerous physical, endocrine and paracrine stimuli in physiological and pathological conditions. Among others signals, osteoresorptive mediators (such as interleukin (IL)-1, IL-6, IL-15, IL-17, IL, 21, IL-33, tumor necrosis factor (TNF)-α and receptor activator of nuclear factor-κB ligand (RANKL), CCL2, CXCL12) produced by inflammatory/immune cells create conditions that promote maturation and function of osteoclasts [1][2][3][4]. Bone resorption and osteolysis are the prominent features and causes of substantial morbidity in inflammatory processes associated with arthritis as well as with localized bacterial infections of bone and adjacent tissues, peri-prosthetic loosening, vasculitis, connective tissue diseases, chronic viral infections and inflammatory bowel diseases [5][6][7][8]. Bone resorption in arthritisInflammatory arthritides comprise a heterogeneous group of joint disorders that are characterized by chronic inflammatory response as we...

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Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis

Cited by 126 publications

References 44 publications

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

CSF-1 Receptor Signaling in Myeloid Cells

Induction of osteoclast progenitors in inflammatory conditions: key to bone destruction in arthritis

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