Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
Institute of Technology, University of Tartu, Tartu, Estonia.
J Virol. 2015 Jan;89(1):581-93. doi: 10.1128/JVI.02034-14. Epub 2014 Oct 22.
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 (μCT) 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-κB 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.
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.
最近，致病的甲病毒（尤其是基孔肯雅病毒）在全球范围内死灰复燃，这凸显出迫切需要开发治疗干预策略。虽然已经在确定甲病毒病的病理生理学方面取得了重大进展，但对于基孔肯雅病毒引起的关节炎的发病机制或治疗感染相关严重关节炎症状的潜在治疗方法知之甚少。在这里，我们使用微计算机断层扫描（μCT）和组织形态计量分析，为 CHIKV 感染小鼠的胫骨近端骺骨体积减少提供了以前未描述的证据，与模拟对照的结果相比。这与感染关节中核因子-κB 配体/骨保护素（RANKL/OPG）比值的显著增加以及 CHIKV 患者血清中的显著增加有关。感染小鼠关节中单核细胞趋化蛋白（MCPs）的表达水平，包括 MCP-1/CCL2、MCP-2/CCL8 和 MCP-3/CCL7，也高度升高，同时胫骨骺骨和踝关节骨髓中的细胞增多。用 MCP 抑制剂 bindarit 治疗可显著降低这种作用和 CHIKV 引起的骨质流失。总的来说，这些发现表明 MCPs 在促进 CHIKV 诱导的破骨细胞形成和疾病期间的骨丢失中具有独特的作用，并表明用 bindarit 抑制 MCPs 可能是治疗受甲病毒诱导的骨质流失的有效方法。
致病的甲病毒，包括基孔肯雅病毒（CHIKV）和罗斯河病毒（RRV），引起了世界各地的多发性关节炎暴发，这种疾病在感染后可在患者中持续数月。以前的研究表明，宿主促炎可溶性因子与 CHIKV 疾病的严重程度有关。此外，已经确定趋化因子（C-C 基序）配体 2（CCL2/MCP-1）在细胞募集和诱导破骨细胞（OC）形成中很重要。在这里，我们表明 CHIKV 在骨骼中复制，并通过增加 RANKL/OPG 比值引发骨质流失。CHIKV 感染导致炎性关节中 MCP 诱导的细胞浸润，并用 MCP 抑制药物 bindarit 治疗可以减轻骨质流失。总的来说，我们的数据揭示了 MCP 在 CHIKV 诱导的骨质流失中以前未被描述的作用：一种是募集单核细胞/OC 前体到关节部位，从而有利于形成促破骨细胞的微环境。这表明 bindarit 可能是治疗人类甲病毒诱导的骨质流失和关节炎的有效方法。
