IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis.
IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis.
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DOI：
10.1186/s13075-016-0998-x
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发表时间：
2016-05-10
影响因子：
4.9
通讯作者：
Gravallese EM
中科院分区：
文献类型：
--
作者：
Shaw AT;Maeda Y;Gravallese EM
白细胞介素-17A（IL-17 A）在包括脊柱关节炎在内的几种风湿性疾病中起致病作用，并且矛盾的是，已被描述为促进和保护骨形成。因此，我们研究了IL-17 A对体外成骨细胞分化和体内炎性关节炎模型中骨膜骨形成的影响。在IL-17 A缺陷型和野生型小鼠中诱导K/BxN血清转移关节炎。临床和组织学炎症进行了评估和骨膜骨形成进行了定量。小鼠颅骨成骨细胞在IL-17 A持续存在的情况下分化，无论是否阻断分泌型卷曲相关蛋白（sFRP）1，并通过qRT-PCR和矿化试验确定对分化的影响。还通过qRT-PCR评估IL-17 A对Wnt信号传导途径拮抗剂表达的影响。最后，在用IL-17 A、TNF或IL-17 A加TNF处理后，评价了Dickkopf（DKK）1在鼠滑膜成纤维细胞中表达的调节。IL-17 A缺陷小鼠在炎症高峰时比野生型小鼠发育出显著更多的骨膜骨，尽管炎症和骨侵蚀的严重程度相当。IL-17 A在体外抑制颅骨成骨细胞分化，诱导成骨细胞中Wnt拮抗剂sFRP 1的mRNA表达，并抑制sFRP 3的表达，两者都可能有助于抑制成骨细胞分化。此外，sFRP 1的阻断抗体降低了IL-17 A对分化的抑制作用。虽然用IL-17 A处理抑制成骨细胞中的DKK 1 mRNA表达，但IL-17 A加TNF协同上调滑膜成纤维细胞中的DKK 1 mRNA表达。IL-17 A可能限制脊柱关节炎中炎症骨膜部位的骨形成程度。IL-17 A抑制颅骨成骨细胞分化，部分通过调节Wnt信号通路组分的表达。这些结果表明，需要进一步研究IL-17 A在脊柱关节炎骨形成中的作用。
Interleukin-17A (IL-17A) plays a pathogenic role in several rheumatic diseases including spondyloarthritis and, paradoxically, has been described to both promote and protect from bone formation. We therefore examined the effects of IL-17A on osteoblast differentiation in vitro and on periosteal bone formation in an in vivo model of inflammatory arthritis. K/BxN serum transfer arthritis was induced in IL-17A-deficient and wild-type mice. Clinical and histologic inflammation was assessed and periosteal bone formation was quantitated. Murine calvarial osteoblasts were differentiated in the continuous presence of IL-17A with or without blockade of secreted frizzled related protein (sFRP)1 and effects on differentiation were determined by qRT-PCR and mineralization assays. The impact of IL-17A on expression of Wnt signaling pathway antagonists was also assessed by qRT-PCR. Finally, regulation of Dickkopf (DKK)1 expression in murine synovial fibroblasts was evaluated after treatment with IL-17A, TNF, or IL-17A plus TNF. IL-17A-deficient mice develop significantly more periosteal bone than wild-type mice at peak inflammation, despite comparable severity of inflammation and bone erosion. IL-17A inhibits calvarial osteoblast differentiation in vitro, inducing mRNA expression of the Wnt antagonist sFRP1 in osteoblasts, and suppressing sFRP3 expression, both potentially contributing to inhibition of osteoblast differentiation. Furthermore, a blocking antibody to sFRP1 reduced the inhibitory effect of IL-17A on differentiation. Although treatment with IL-17A suppresses DKK1 mRNA expression in osteoblasts, IL-17A plus TNF synergistically upregulate DKK1 mRNA expression in synovial fibroblasts. IL-17A may limit the extent of bone formation at inflamed periosteal sites in spondyloarthritis. IL-17A inhibits calvarial osteoblast differentiation, in part by regulating expression of Wnt signaling pathway components. These results demonstrate that additional studies focusing on the role of IL-17A in bone formation in spondyloarthritis are indicated.