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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis
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Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis

机译：富含脯氨酸的酪氨酸激酶2调节骨祖细胞和骨形成，并为骨质疏松症提供合成代谢治疗方法

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摘要

Bone is accrued and maintained primarily through the coupled actions of bone-forming osteoblasts and bone-resorbing oste-oclasts. Cumulative in vitro studies indicated that proline-rich tyrosine kinase 2 (PYK2) is a positive mediator of osteoclast function and activity. However, our investigation of PYK2-/- mice did not reveal evidence supporting an essential function for PYK2 in osteoclasts either in vivo or in culture. We find that PYK2-/-mice have high bone mass resulting from an unexpected increase in bone formation. Consistent with the in vivo findings, mouse bone marrow cultures show that PYK2 deficiency enhances differentiation and activity of osteoprogenitor cells, as does expressing a PYK2-specific short hairpin RNA or dominantly interfering proteins in human mesenchymal stem cells. Furthermore, the daily administration of a small-molecule PYK2 inhibitor increases bone formation and protects against bone loss in ovariectomized rats, an established preclinical model of postmenopausal osteoporosis. In summary, we find that PYK2 regulates the differentiation of early osteoprogenitor cells across species and that inhibitors of the PYK2 have potential as a bone anabolic approach for the treatment of osteoporosis.
机译：骨骼的产生和维持主要是通过成骨的成骨细胞和骨吸收性破骨细胞的耦合作用来进行的。累积的体外研究表明，富含脯氨酸的酪氨酸激酶2（PYK2）是破骨细胞功能和活性的积极介体。但是，我们对PYK2-/-小鼠的研究没有发现支持PYK2在破骨细胞体内或培养中具有必不可少功能的证据。我们发现PYK2-/-小鼠的骨量很高，这是由于骨形成的意外增加所致。与体内发现一致，小鼠骨髓培养物显示PYK2缺乏症增强了骨祖细胞的分化和活性，正如在人间充质干细胞中表达PYK2特异性短发夹RNA或主要干扰蛋白质一样。此外，每天服用小分子PYK2抑制剂可增加去卵巢大鼠的骨形成并防止骨质流失，这是已建立的绝经后骨质疏松症的临床前模型。总而言之，我们发现PYK2调节了跨物种的早期骨祖细胞的分化，并且PYK2抑制剂具有作为骨合成代谢方法治疗骨质疏松症的潜力。

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