Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin
Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin
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DOI：
10.1172/jci60975
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发表时间：
2012-05-01
影响因子：
15.9
通讯作者：
Schett, Georg
中科院分区：
文献类型：
--
作者：
Harre, Ulrike;Georgess, Dan;Schett, Georg
自身免疫性并发骨质流失。在人类类风湿性关节炎（RA）中，最严重的炎性关节疾病，抗瓜氨酸化蛋白的自身抗体是骨破坏的最强风险因素之一。因此，我们假设这些自身抗体直接影响骨代谢。在此，我们发现抗瓜氨酸化蛋白自身抗体与类风湿关节炎患者破骨细胞介导的骨吸收血清标志物之间存在强而特异的相关性。此外，人类破骨细胞表达的酶诱导蛋白瓜氨酸，和特定的N-末端的波形蛋白瓜氨酸诱导破骨细胞分化过程中。针对突变的瓜氨酸波形蛋白（MCV）的亲和纯化的人自身抗体不仅与破骨细胞表面结合，而且还导致破骨细胞生成和骨吸收活性的强烈诱导。将纯化的人MCV自身抗体连续转移到小鼠中诱导骨质减少和破骨细胞生成增加。这种效应是基于TNF-α从破骨细胞前体的诱导性释放和破骨细胞前体细胞数量的随后增加以及活化和生长因子受体表达的增强。因此，我们的数据表明，瓜氨酸波形蛋白反应的自身抗体形成直接诱导骨丢失，提供了适应性免疫系统和骨之间的联系。
Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-alpha from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone.