Osteocyte control of bone formation via sclerostin, a novel BMP antagonist
Osteocyte control of bone formation via sclerostin, a novel BMP antagonist
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DOI：
10.1093/emboj/cdg599
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发表时间：
2003-12-01
期刊：
影响因子：
11.4
通讯作者：
Latham, JA
中科院分区：
文献类型：
--
作者：
Winkler, DG;Sutherland, MK;Latham, JA
还有一种尚未得到满足的医学需求，那就是用合成代谢疗法来修复丢失的骨骼。人类遗传性骨病提供了对骨调节过程的洞察。硬化性骨质疏松症是一种典型的疾病，其特征是由于SOST表达的丧失而导致骨量增加。作为Sost基因蛋白产物的skerostin与骨形态发生蛋白(BMP)受体I型和II型竞争结合BMPs，减少BMP信号转导，抑制成骨细胞矿化。在培养的成骨细胞和骨骼的矿化区域检测到SOST的表达，但在破骨细胞中检测不到。在骨细胞中的强烈表达表明，这些中央调节细胞表达的硬化素介导了骨的动态平衡。过量表达SOST的转基因小鼠表现出低骨量和骨强度降低，这是成骨细胞活性显著降低和随后骨形成的结果。这种骨细胞来源的负信号的调节在治疗上与骨丢失相关的疾病相关。
There is an unmet medical need for anabolic treatments to restore lost bone. Human genetic bone disorders provide insight into bone regulatory processes. Sclerosteosis is a disease typified by high bone mass due to the loss of SOST expression. Sclerostin, the SOST gene protein product, competed with the type I and type II bone morphogenetic protein (BMP) receptors for binding to BMPs, decreased BMP signaling and suppressed mineralization of osteoblastic cells. SOST expression was detected in cultured osteoblasts and in mineralizing areas of the skeleton, but not in osteoclasts. Strong expression in osteocytes suggested that sclerostin expressed by these central regulatory cells mediates bone homeostasis. Transgenic mice overexpressing SOST exhibited low bone mass and decreased bone strength as the result of a significant reduction in osteoblast activity and subsequently, bone formation. Modulation of this osteocyte-derived negative signal is therapeutically relevant for disorders associated with bone loss.