Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis
Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis
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DOI：
10.1002/art.22941
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发表时间：
2007-10-01
影响因子：
--
通讯作者：
Muneta, Takeshi
中科院分区：
文献类型：
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作者：
Shimizu, Sadanori;Asou, Yoshinori;Muneta, Takeshi
目标。目的探讨破骨细胞生成抑制因子/骨保护素(OPG)在体内对软骨细胞在骨性关节炎(OA)发病过程中的作用。为了确定内源性OPG在骨性关节炎发生发展中的作用，通过手术诱导OPG(+/-)小鼠及其野生型(WT)仔鼠的骨性关节炎。为确定外源性OPG的作用，将重组人OPG(RHuOPG)或赋形剂每周5次注入C57BL/6J小鼠膝关节。诱导4周后处死所有小鼠，取关节进行免疫组织化学检测。虽然WT和OPG(+/-)小鼠均可引起骨关节炎的改变，但OPG(+/-)小鼠关节软骨的退行性改变显著增强。在手术诱导的C57BL/6J小鼠中，关节内注射OPG可以保护关节软骨免受OA的进展。OPG组动物的Mankin和软骨破坏评分与对照组的50%相似。此外，OPG对关节软骨厚度有明显保护作用。原位末端标记法检测结果表明，rHuOPG可抑制手术诱导的骨性关节炎关节软骨细胞的凋亡。免疫组织化学染色结果显示，OPG治疗组滑膜和软骨细胞中OPG蛋白的表达水平均高于对照组。这些数据表明，内源性OPG对OA进展过程中发生的软骨破坏具有保护作用。此外，将rHuOPG直接注射到关节软骨细胞中，通过防止软骨细胞凋亡，防止了实验性骨性关节炎小鼠的软骨破坏。
Objective. To investigate the effect of osteoclastogenesis inhibitory factor/osteoprotegerin (OPG) on chondrocytes in the development of osteoarthritis (OA) in vivo.Methods. To determine the role of endogenous OPG in the progression of OA, OA was surgically induced in OPG(+/-) mice and their wild-type (WT) littermates. To determine the role of exogenous OPG, knee joints of C57BL/6J mice with surgically induced OA were injected intraarticularly with recombinant human OPG (rHuOPG) or vehicle 5 times a week. All mice were euthanized 4 weeks after OA induction; joints were harvested and evaluated immunohistochemically.Results. Although OA changes were induced in both WT and OPG(+/-) mice, the degenerative changes in the articular cartilage were significantly enhanced in OPG(+/-) mice. In C57BL/6J mice with surgically induced OA, intraarticular OPG administration protected the articular cartilage from the progression of OA. The Mankin and cartilage destruction scores in OPG-treated animals were similar to 50% of those seen in the control group. Furthermore, OPG administration significantly protected articular cartilage thickness. Findings of the TUNEL assay indicated that rHuOPG prevented chondrocyte apoptosis in joints with surgically induced OA. Results of immunostaining indicated that OPG protein was detected in the synovium and in resident chondrocytes at higher levels in the OPG-treated group than in the control group.Conclusion. These data indicate that endogenous OPG had a protective effect against the cartilage destruction that occurs during OA progression. Furthermore, direct administration of rHuOPG to articular chondrocytes prevented cartilage destruction in an experimental murine model of OA via prevention of chondrocyte apoptosis.