Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity
Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity
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DOI：
10.1074/jbc.m301716200
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发表时间：
2003-06-27
影响因子：
4.8
通讯作者：
Itoh, N
中科院分区：
文献类型：
--
作者：
Kusu, N;Laurikkala, J;Itoh, N
硬化症是一种进行性硬化性骨发育不良。Sclerostin（SOST基因）最初被鉴定为引起骨质疏松的基因。然而，sclerostin的生理作用仍有待阐明。硬化蛋白在小鼠胚胎骨发育过程中有强烈表达。sclerostin的点状表达定位于膜内形成的颅骨和软骨内形成的长骨的表面上。硬化蛋白阳性细胞被鉴定为破骨细胞。在培养的细胞中产生的重组sclerostin蛋白作为单体被有效地分泌。我们检测了sclerostin对小鼠前成骨细胞MC 3 T3-E1细胞BMP 2、BMP 4、BMP 6和BMP 7活性的影响。Sclerostin抑制BMP 6和BMP 7的活性，但不抑制BMP 2和BMP 4的活性。硬化蛋白以高亲和力结合BMP 6和BMP 7，但以低亲和力结合BMP 2和BMP 4。总之，sclerostin是一种新型的分泌型破骨细胞源性BMP拮抗剂，具有独特的配体特异性。我们认为sclerostin通过抑制BMP诱导的成骨细胞的分化和/或功能来负性调节骨的形成。由于sclerostin的表达局限于骨吸收破骨细胞，它提供了一种机制，从而抑制骨附着在附近的吸收。我们的研究结果表明，sclerostin在骨重建中起着重要作用，并连接骨吸收和骨沉积。
Sclerosteosis is a progressive sclerosing bone dysplasia. Sclerostin (the SOST gene) was originally identified as the sclerosteosis-causing gene. However, the physiological role of sclerostin remains to be elucidated. Sclerostin was intensely expressed in developing bones of mouse embryos. Punctuated expression of sclerostin was localized on the surfaces of both intramembranously forming skull bones and endochondrally forming long bones. Sclerostin-positive cells were identified as osteoclasts. Recombinant sclerostin protein produced in cultured cells was efficiently secreted as a monomer. We examined effects of sclerostin on the activity of BMP2, BMP4, BMP6, and BMP7 for mouse preosteoblastic MC3T3-E1 cells. Sclerostin inhibited the BMP6 and BMP7 activity but not the BMP2 and BMP4 activity. Sclerostin bound to BMP6 and BMP7 with high affinity but bound to BMP2 and BMP4 with lower affinity. In conclusion, sclerostin is a novel secreted osteoclast-derived BMP antagonist with unique ligand specificity. We suggest that sclerostin negatively regulates the formation of bone by repressing the differentiation and/or function of osteoblasts induced by BMPs. Since sclerostin expression is confined to the bone-resorbing osteoclast, it provides a mechanism whereby bone apposition is inhibited in the vicinity of resorption. Our findings indicate that sclerostin plays an important role in bone remodeling and links bone resorption and bone apposition.