Mechanisms of TNF-α- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis
Mechanisms of TNF-α- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis
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DOI：
10.1172/jci200316069
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发表时间：
2003-03-01
影响因子：
15.9
通讯作者：
Schwarz, EM
中科院分区：
文献类型：
--
作者：
Ritchlin, CT;Haas-Smith, SA;Schwarz, EM
银屑病关节炎（PsA）是一种以广泛骨吸收为特征的炎性关节疾病。这种基质损失的机制尚未阐明。我们在这里报告说，血液样本PsA患者，特别是那些与骨侵蚀可见平片，表现出显着增加破骨细胞前体（OCPs）与健康对照组相比。此外，PsA PBMC在没有外源性NF-κ B配体受体激活剂（RANKL）或MCSF的情况下容易在体外形成破骨细胞。骨保护素（OPG）和抗TNF抗体抑制破骨细胞的形成。此外，培养的PsA PBMC自发分泌比健康对照更高水平的TNF-α。在体内，OCP频率大幅下降PsA患者治疗后，抗TNF药物。免疫组化分析显示，PsA标本中的软骨下骨和滑膜RANK阳性血管周围单核细胞和破骨细胞。RANKL表达在滑膜衬里层中显著上调，而OPG免疫染色仅限于内皮。这些结果为了解银屑病侵袭性骨侵蚀的发病机制提供了一个模型。OCP由TNF-α活化的PBMC产生，这些PBMC迁移至发炎的滑膜和软骨下骨，在那里它们暴露于未对抗的RANKL和TNF-α。这导致在侵蚀前部和软骨下骨中的破骨细胞生成，导致对银屑病骨的双向攻击。
Psoriatic arthritis (PsA) is an inflammatory joint disease characterized by extensive bone resorption. The mechanisms underlying this matrix loss have not been elucidated. We report here that blood samples from PsA patients, particularly those with bone erosions visible on plain radiographs, exhibit a marked increase in osteoclast precursors (OCPs) compared with those from healthy controls. Moreover, PsA PBMCs readily formed osteoclasts in vitro without exogenous receptor activator of NF-kappaB ligand (RANKL) or MCSF. Both osteoprotegerin (OPG) and anti-TNF antibodies inhibited osteoclast formation. Additionally, cultured PsA PBMCs spontaneously secreted higher levels of TNF-alpha than did healthy controls. In vivo, OCP frequency declined substantially in PsA patients following treatment with anti-TNF agents. Immunohistochemical analysis of subchondral bone and synovium revealed RANK-positive perivascalar mononuclear cells and osteoclasts in PsA specimens. RANKL expression was dramatically upregulated in the synovial lining layer, while OPG immunostaining was restricted to the endothelium. These results suggest a model for understanding the pathogenesis of aggressive bone erosions in PsA. OCPs arise from TNF-alpha-activated PBMCs that migrate to the inflamed synovium and subchondral bone, where they are exposed to unopposed RANKL and TNF-alpha. This leads to osteoclastogenesis at the erosion front and in subchondral bone, resulting in a bidirectional assault on psoriatic bone.