Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone
Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone
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DOI：
10.1172/jci6610
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发表时间：
1999-08-01
影响因子：
15.9
通讯作者：
Manolagas, SC
中科院分区：
文献类型：
--
作者：
Jilka, RL;Weinstein, RS;Manolagas, SC
再生组织（如骨）的质量在很大程度上取决于执行细胞的数量，而执行细胞的数量又由祖细胞的复制速率和成熟细胞的寿命决定，这反映了细胞凋亡导致的死亡时间。间歇性给予甲状旁腺激素（PTH）可增加骨量，但这种现象的机制一直不清楚。我们报道，在骨量正常或因成骨细胞生成缺陷而患有骨质减少的小鼠中，每日注射PTH可增加骨形成，但不影响新成骨细胞的产生。相反，PTH通过防止成熟成骨细胞凋亡来延长其寿命——在正常情况下，大多数这些细胞的命运是凋亡。PTH的抗凋亡作用足以解释骨量的增加，并且在体外使用啮齿动物和人类的成骨细胞及骨细胞得到了证实。这一证据证明了一个基本原理，即通过抑制细胞凋亡可以增加细胞群体所完成的工作。此外，它为骨质疏松症以及可能的其他因组织量减少而损害功能完整性的病理状况提出了新的药物治疗策略。
The mass of regenerating tissues, such as bone, is critically dependent on the number of executive cells, which in turn is determined by the rate of replication of progenitors and the life-span of mature cells, reflecting the timing of death by apoptosis. Bone mass can be increased by intermittent parathyroid hormone (PTH) administration, but the mechanism of this phenomenon has remained unknown. We report that daily PTH injections in mice with either normal bone mass or osteopenia due to defective osteoblastogenesis increased bone formation without affecting the generation of new osteoblasts. Instead, PTH increased the life-span of mature osteoblasts by preventing their apoptosis - the fate of the majority of these cells under normal conditions. The antiapoptotic effect of PTH was sufficient to account for the increase in bone mass, and was confirmed in vitro using rodent and human osteoblasts and osteocytes. This evidence provides proof of the basic principle that the work performed by a cell population can be increased by suppression of apoptosis. Moreover, it suggests novel pharmacotherapeutic strategies for osteoporosis and, perhaps, other pathologic conditions in which tissue mass diminution has compromised functional integrity.