Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification
Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification
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DOI：
10.1016/s0002-9440(10)64482-3
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发表时间：
2002-12-01
影响因子：
6
通讯作者：
Giachelli, CM
中科院分区：
文献类型：
--
作者：
Steitz, SA;Speer, MY;Giachelli, CM
异位钙化，软组织的异常钙化，可具有严重的临床后果，特别是当局限于重要器官如心脏瓣膜、动脉和肾脏时。最近的观察表明，异位钙化，像骨生物矿化，是一个积极调控的过程。这些观察结果导致了对异位钙化分子决定因素的研究。骨桥蛋白（OPN）是一种与正常和病理性矿物质沉积相关的分泌性磷蛋白，是一种候选分子。在本研究中，发现OPN是体内异位钙化的天然抑制剂。与野生型小鼠相比，皮下植入OPN缺失小鼠后，戊二醛固定的主动脉瓣瓣叶显示出加速的钙化，并且钙化增加了四倍至五倍。体外和体内研究表明，OPN不仅抑制矿物质沉积，而且通过物理阻断羟基磷灰石晶体生长和诱导单核细胞中碳酸酐酶H的表达以及促进细胞外环境的酸化来积极促进其溶解。这些发现提示了OPN作用的新机制和治疗异位钙化的潜在治疗方法。
Ectopic calcification, the abnormal calcification of soft tissues, can have severe clinical consequences especially when localized to vital organs such as heart valves, arteries, and kidneys. Recent observations suggest that ectopic calcification, like bone biomineralization, is an actively regulated process. These observations have led a search for molecular determinants of ectopic calcification. A candidate molecule is osteopontin (OPN), a secreted phosphoprotein invariantly associated with both normal and pathological mineral de posits. In the present study, OPN was found to he a natural inhibitor of ectopic calcification in vivo. Glutaraldehyde-fixed aortic valve leaflets showed accelerated and fourfold to fivefold greater calcification after subcutaneous implantation into OPN-null mice compared to wild-type mice. In vitro and in vivo studies suggest that OPN not only inhibits mineral deposition but also actively promotes its dissolution by physically blocking hydroxyapatite crystal growth and inducing expression of carbonic anhydrase H in monocytic cells and promoting acidification of the extracellular milieu. These findings suggest a novel mechanism of OPN action and potential therapeutic approach to the treatment of ectopic calcification.