Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis.
Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis.
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DOI：
10.1172/jci16069
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发表时间：
2003-03
期刊：
影响因子：
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通讯作者：
C. Ritchlin;S. Haas-Smith;Ping Li;D. Hicks;E. Schwarz
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文献类型：
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作者：
C. Ritchlin;S. Haas-Smith;Ping Li;D. Hicks;E. Schwarz
银屑病关节炎（PsA）是一种以广泛骨吸收为特征的炎症性关节疾病。这种基质损失的机制尚未阐明。我们在此报告，与健康对照者相比，银屑病关节炎患者的血液样本，特别是那些在平片上可见骨侵蚀的患者，显示出破骨细胞前体（OCP）显着增加。此外，PsA PBMC 在体外无需外源 NF-κB 配体受体激活剂 (RANKL) 或 MCSF 即可轻松形成破骨细胞。骨保护素 (OPG) 和抗 TNF 抗体均抑制破骨细胞形成。此外，培养的 PsA PBMC 自发分泌的 TNF-α 水平高于健康对照。在体内，使用抗 TNF 药物治疗后，PsA 患者的 OCP 频率大幅下降。软骨下骨和滑膜的免疫组织化学分析显示 PsA 标本中存在 RANK 阳性血管周围单核细胞和破骨细胞。滑膜衬里层中的 RANKL 表达显着上调，而 OPG 免疫染色仅限于内皮细胞。这些结果提出了一个了解银屑病关节炎侵袭性骨侵蚀发病机制的模型。 OCP 由 TNF-α 激活的 PBMC 产生，迁移到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。这导致侵蚀前沿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 perivascular 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.