MCP-1 expressed by osteoclasts stimulates osteoclastogenesis in an autocrine/paracrine manner

Miyamoto, Kana; Ninomiya, Ken; Sonoda, Koh Hei; Miyauchi, Yoshiteru; Hoshi, Hiroko; Iwasaki, Ryuichiro; Miyamoto, Hiroaki; Yoshida, Shigeyuki; Sato, Yuiko; Morioka, Hideo; Chiba, Kazuhiro; Egashira, Kensuke; Suda, Toshio; Toyama, Yoshiaki; Miyamoto, Takeshi

doi:10.1016/j.bbrc.2009.04.020

Cited by 79 publications

(73 citation statements)

References 34 publications

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“…High levels of CCL8 and CCL7 have been detected in synovial tissues of individuals suffering from RA, osteoarthritis, and reactive arthritis (37). Studies in CCL2-deficient mice and human peripheral blood mononuclear cells (PBMCs) have shown CCL2 to be an osteoclastogenic factor (38,39). PBMCs from RA patients showed a higher osteoclastogenic potential than those of healthy controls, and this correlated positively to serum levels of CCL2 (40).…”

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confidence: 99%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

105

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The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (CT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-B ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.

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mentioning

confidence: 99%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

105

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“…Finally, in their work the lavage was shown to have an increased amount of chemokine C-C motif ligand-2 (CCL2) relative to that in control littermates. As altered levels of cytokines and chemokines, including CCL2 [22], can influence osteoclastogenesis, the reduced bone volume in these mice may be related to an inherent inflammatory state in CF mice. Supporting this conjecture is the work of Haworth et al [23], who showed bone mineral content measures to be negatively correlated with serum interleukin-6 and C reactive protein levels in CF patients.…”

Section: Discussionmentioning

confidence: 97%

Osteopenia in Cftr-deltaF508 mice

Paradis¹,

Wilke²,

Haston³

2010

Journal of Cystic Fibrosis

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“…Also, CCL2 was highly induced with OC maturation, with the positive correlation between OC CCL2 expression and the number of OCs differentiated from SFMC. It has been shown, using CCL2-deficient mice and human PBMC, that CCL2 regulates OC differentiation in an autocrine/paracrine manner and that OCPs express CCL2 receptors, CCR2 and CCR4 [13,14]. Kim et al proposed that RANKL-stimulated OC-lineage cells send CCL2 chemokine signal to attract OCPs to the site of RANKL signaling, resulting in cell fusion to multinuclear OCs [15].…”

Section: Discussionmentioning

confidence: 99%

Association of systemic and intra-articular osteoclastogenic potential, pro-inflammatory mediators and disease activity with the form of inflammatory arthritis

Ikić¹,

Jajić²,

Lazić³

et al. 2013

International Orthopaedics (SICOT)

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Purpose We aimed to assess osteoclastogenic potential of peripheral blood mononuclear cells (PBMC) and synovial fluid-derived mononuclear cells (SFMC) in different forms of arthritis and to correlate it with inflammatory mediators within intra-articular and circulatory compartments. Methods Paired PBMC and SFMC samples of patients with rheumatoid arthritis (RA; n =10) and psoriatic arthritis (PsA; n =10), and PBMC of healthy controls were cultured to assess osteoclastogenic potential by the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) and expression of OC-related genes (receptor activator of nuclear factor-κΒ (RANK), cFMS, and TRAP). Osteoclastogenesis was correlated with the arthritis-related inflammatory indicators in serum and synovial fluid (SF). Results Number of OCs differentiated from PBMC was significantly higher in RA and PsA compared with control, with RA having more OCs compared with PsA. There was no difference in SFMC OC number between arthritic patients, but RANK expression in OCs differentiated from SFMC was higher in PsA compared with RA. SF of PsA patients more potently induced OC differentiation from control CD3 + PBMC compared with RA, paralleled with higher RANK-ligand expression in PsA SFMC. Positive correlations of OC number with erythrocyte sedimentation rate, serum level of CCL2, and PBMC gene expression of interleukin-18 and Fas-ligand were observed. Conclusion Osteoclastogenic potential is systemically enhanced in patients with RA, paralleled by disordered systemic and local expression of proinflammatory mediators, whereas PsA involves specific deregulation in RANKL/RANK axis. Our study reveals arthritis-specific mediators associated with the form of arthritis, indicating clinical relevance for diagnosis and treatment.

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MCP-1 expressed by osteoclasts stimulates osteoclastogenesis in an autocrine/paracrine manner

Cited by 79 publications

References 34 publications

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Osteopenia in Cftr-deltaF508 mice

Association of systemic and intra-articular osteoclastogenic potential, pro-inflammatory mediators and disease activity with the form of inflammatory arthritis

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