IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis
IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis
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DOI：
10.1172/jci5703
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发表时间：
1999-05-01
影响因子：
15.9
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Kotake, S;Udagawa, N;Suda, T
IL-17是新近发现的一种T细胞源性细胞因子，其在破骨细胞发育中的作用尚未完全阐明。用重组人IL-17处理小鼠造血细胞和原代成骨细胞共培养，诱导形成多核细胞，这些细胞满足破骨细胞的主要标准，包括抗酒石酸酸性磷酸酶活性、降钙素受体和牙本质切片上的凹坑形成。IL-17诱导的破骨细胞生成需要破骨祖细胞与成骨细胞的直接相互作用，这种作用可被吲哚美辛或环氧合酶-2(COX-2)选择性抑制剂NS398完全抑制。加入IL-17可促进骨髓细胞与成骨细胞共培养和成骨细胞单独培养中前列腺素E-2(PGE(2))的合成，但对骨髓细胞单独培养中前列腺素E-2的合成无明显影响。此外，IL-17剂量依赖性地诱导成骨细胞表达破骨细胞分化因子(ODF)。ODF是一种膜相关蛋白，它向破骨细胞前体细胞传递必要的信号(S)，使其分化为破骨细胞。ODF诱骗受体破骨细胞生成抑制因子(OCIF)可完全抑制IL-17诱导的破骨细胞分化。类风湿关节炎(RA)患者滑液中IL-17水平显著高于骨性关节炎(OA)患者。抗IL-17抗体可显著抑制RA滑膜组织培养上清液诱导的破骨细胞形成。这些结果表明，IL-17首先作用于成骨细胞，刺激COX-2依赖的PGE(2)合成和ODF基因表达，进而诱导破骨祖细胞向成熟破骨细胞分化，IL-17是RA患者破骨细胞性骨吸收的关键细胞因子。
IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E-2 (PGE(2)) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE(2) synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.