Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis
Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis
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DOI：
10.1002/art.23638
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发表时间：
2008-08-01
影响因子：
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通讯作者：
Cohen-Solal, M. E.
中科院分区：
文献类型：
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作者：
Kadri, A.;Ea, H. K.;Cohen-Solal, M. E.
目标。在实验性骨关节炎(OA)的小鼠模型中，表征骨微结构的变化，并验证破坏局部细胞因子平衡可以改变软骨退化的假说。10周龄雄性C57BL/6小鼠右膝内侧半月板切除，左膝假手术。小鼠腹腔注射护骨素(OPG)(10 mg/kg)、白介素1受体拮抗剂(IL-1ra)(100 mg/kg)或磷酸盐缓冲生理盐水，连续6周。观察骨小梁的微结构、骨性关节炎评分以及ADAMTS-4和ADAMTS-5的表达。在IL-1ra和OPG存在的情况下，测定软骨组织培养中蛋白多糖的释放。半月板切除组膝关节骨体积/组织体积(WIN)低于假手术组，而骨小梁分离度、骨性关节炎评分和聚集酶表达高于假手术组。经OPG治疗后，半月板切除组的BV/TV显著增加，骨小梁分离减少。OPG可显著降低OA评分和ADAMTS阳性细胞数，而IL-1ra对其无明显影响。此外，OPG不能直接减少软骨外植体培养中蛋白多糖的释放。在一个实验性的骨性关节炎模型中，半月板切除在6周时导致骨丢失和软骨退化。在体内，全身应用OPG可阻止骨和软骨的降解，但在体外对软骨无影响。这些数据共同表明，骨可能在骨关节炎发病的早期阶段起作用。他们进一步提示，RANKL/OPG平衡的破坏可能会导致软骨在机械负荷下的退化。骨细胞因子网络的特异性靶向可能有助于预防骨性关节炎。
Objective. To characterize bone microarchitectural changes and to test the hypothesis that disrupting local cytokine equilibrium could modify cartilage degradation in a murine model of experimental osteoarthritis (OA).Methods. Ten-week-old male C57BL/6 mice underwent medial meniscectomy of their right knees and a sham operation of their left knees. The mice received intraperitoneal injections of osteoprotegerin (OPG) (10 mg/kg), interleukin-1 receptor antagonist (IL-1Ra) (100 mg/kg), or phosphate buffered saline for 6 weeks. The microarchitecture of the trabecular bone, the OA score, and expression of ADAMTS-4 and ADAMTS-5 were assessed. Proteoglycan release was measured in cartilage explant cultures in the presence of IL-1Ra and OPG.Results. In the meniscectomized knees, bone volume/tissue volume (WIN) was lower, whereas trabecular separation, the OA score, and aggrecanase expression were higher than in the sham-operated knees. After treatment with OPG, BV/TV was significantly increased and trabecular separation was reduced in the knees that underwent meniscectomy. The OA score and the number of ADAMTS-positive cells were significantly decreased by treatment with OPG but were not affected by IL-1Ra. Moreover, OPG did not directly reduce the release of proteoglycans from cartilage explant cultures.Conclusion. In an experimental model of OA, meniscectomy induced bone loss and cartilage degradation at 6 weeks. Systemic administration of OPG prevented bone and cartilage degradation in vivo but had no effect on cartilage in vitro. These data collectively indicate that bone could be a contributor in the early stages of OA pathogenesis. They further suggest that disruption of RANKL/OPG balance might result in the degradation of cartilage subjected to mechanical loading. Specific targeting of the bone cytokine network might help to prevent OA.