Raymond Purves Bone and Joint Research Labs, Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
Osteoarthritis Cartilage. 2011 Jul;19(7):874-85. doi: 10.1016/j.joca.2011.04.014. Epub 2011 May 12.
To investigate the regulation of sclerostin (SOST) in osteoarthritis (OA) and its potential effects on articular cartilage degradation.
SOST and other Wnt-β-catenin components were immuno-localised in osteochondral sections of surgically-induced OA in knees of sheep and mice, and human OA samples obtained at arthroplasty. Regulation of SOST mRNA and protein expression by ovine chondrocytes in response to interleukin-1α (IL-1α) or tumour necrosis factor-α (TNFα) was examined in explant cultures. The effect of 25 or 250 ng/ml recombinant SOST alone or in combination with IL-1α, on ovine articular cartilage explant aggrecan degradation, and chondrocyte gene expression of Wnt-β-catenin pathway proteins, metalloproteinases and their inhibitors, and cartilage matrix proteins was quantified.
Contrary to being an osteocyte-specific protein, SOST was expressed by articular chondrocytes, and mRNA levels were upregulated in vitro by IL-1α but not TNFα. Chondrocyte SOST staining was significantly increased only in the focal area of cartilage damage in surgically-induced OA in sheep and mice, as well as end-stage human OA. In contrast, osteocyte SOST was focally decreased in the subchondral bone in sheep OA in association with bone sclerosis. SOST was biologically active in chondrocytes, inhibiting Wnt-β-catenin signalling and catabolic metalloproteinase [matrix metalloproteinases (MMP) and distintegrin and metalloproteinase with thrombospndin repeats (ADAMTS)] expression, but also decreasing mRNA levels of aggrecan, collagen II and tissue inhibitors of metalloproteinaes (TIMPs). Despite this mixed effect, SOST dose-dependently inhibited IL-1α-stimulated cartilage aggrecanolysis in vitro.
These results implicate SOST in regulating the OA disease processes, but suggest opposing effects by promoting disease-associated subchondral bone sclerosis while inhibiting degradation of cartilage.
研究骨硬化蛋白（SOST）在骨关节炎（OA）中的调节作用及其对关节软骨降解的潜在影响。
在羊和鼠膝关节手术诱导的 OA 及人工关节置换的 OA 患者的骨软骨切片中，免疫定位 SOST 及其它 Wnt-β-连环蛋白成分。在关节软骨细胞的 explant 培养中，检测白细胞介素-1α（IL-1α）或肿瘤坏死因子-α（TNFα）对 SOST mRNA 和蛋白表达的调节作用。单独或与 IL-1α联合使用 25 或 250ng/ml 重组 SOST，对羊关节软骨 explant 聚集蛋白降解以及软骨细胞 Wnt-β-连环蛋白通路蛋白、金属蛋白酶及其抑制剂和软骨基质蛋白的基因表达的影响进行定量分析。
与成骨细胞特异性蛋白相反，SOST 由关节软骨细胞表达，并且在体外由 IL-1α而不是 TNFα上调其 mRNA 水平。仅在羊和鼠手术诱导的 OA 以及终末期人类 OA 的软骨损伤的局灶区域中，软骨细胞 SOST 染色显著增加。相比之下，在与骨硬化相关的羊 OA 中，骨细胞 SOST 局灶性减少。SOST 在软骨细胞中具有生物学活性，抑制 Wnt-β-连环蛋白信号传导和分解代谢金属蛋白酶[基质金属蛋白酶（MMP）和金属蛋白酶与凝血酶重复序列（ADAMTS）]的表达，还降低聚集蛋白、胶原 II 和金属蛋白酶组织抑制剂（TIMPs）的 mRNA 水平。尽管有这种混合作用，但 SOST 剂量依赖性地抑制了体外 IL-1α刺激的软骨聚集蛋白降解。
这些结果表明 SOST 参与调节 OA 疾病进程，但表明通过促进与疾病相关的软骨下骨硬化同时抑制软骨降解来发挥相反的作用。
