Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone
Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone
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DOI：
10.1101/gad.1276205
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发表时间：
2005-05-01
影响因子：
10.5
通讯作者：
Karsenty, G
中科院分区：
文献类型：
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作者：
Murshed, M;Harmey, D;Karsenty, G
细胞外基质矿化是骨的生理过程，也是软组织的病理过程。骨外基质矿化对骨生理的空间限制机制尚不清楚。在这里，我们表明骨矿化需要正常的细胞外磷酸盐浓度，而降低该浓度可阻止任何ECM的矿化。然而，仅仅提高细胞外磷酸盐浓度不足以诱导病理性矿化，这是因为所有ecm中都存在焦磷酸盐，一种矿化抑制剂。ECM矿化只发生在骨中，因为I型胶原蛋白和Tnap（一种裂解焦磷酸盐的酶）只在成骨细胞中共表达。这种双重要求解释了为什么在产生纤维性胶原的细胞中，Tnap异位表达足以诱导病理性矿化。本研究揭示了成骨细胞中广泛表达的基因的共表达是诱导骨矿化的必要和充分条件，并提供了通过调节细胞外磷酸盐浓度可以防止病理性矿化的证据。
Extracellular matrix (ECM) mineralization is a physiological process in bone and a pathological one in soft tissues. The mechanisms determining the spatial restriction of ECM mineralization to bone physiologically are poorly understood. Here we show that a normal extracellular phosphate concentration is required for bone mineralization, while lowering this concentration prevents mineralization of any ECM. However, simply raising extracellular phosphate concentration is not sufficient to induce pathological mineralization, this is because of the presence in all ECMs of pyrophosphate, an inhibitor of mineralization. ECM mineralization occurs only in bone because of the exclusive coexpression in osteoblasts of Type I collagen and Tnap, an enzyme that cleaves pyrophosphate. This dual requirement explains why Tnap ectopic expression in cells producing fibrillar collagen is sufficient to induce pathological mineralization. This study reveals that coexpression in osteoblasts of otherwise broadly expressed genes is necessary and sufficient to induce bone mineralization and provides evidence that pathological mineralization can be prevented by modulating extracellular phosphate concentration.