Molecular mechanism of osteoclastic bone resorption by glucocorticoid-induced osteoporosis in childhood.

为了研究p130 Cas在破骨细胞骨吸收中的作用，我们建立了破骨细胞特异性p130 Cas条件性敲除（p130 CasOCL-）小鼠。p130 CasOCL-小鼠表现出由多核化和细胞骨架组织缺陷引起的高骨量表型，导致骨吸收缺陷。来自p130 CasOCL-小鼠的骨髓细胞能够在体外分化为破骨细胞。然而，p130 CasOCL-小鼠的破骨细胞不能在牙本质切片上形成肌动蛋白环和再吸收陷窝。虽然破骨细胞附着的初始事件，如整合素或Src磷酸化，是完整的，组织肌动蛋白细胞骨架的Rac 1活性降低，其分布在p130 CasOCL-破骨细胞中被破坏。Dock 5是Rho家族的鸟嘌呤核苷酸交换器，在p130 Cas不存在的情况下，Dock 5不能与破骨细胞中的Src或Pyk 2结合。这些结果有力地表明p130 Cas在骨细胞骨吸收中起关键作用。

To investigate the role of p130Cas on osteoclastic bone resorption, we generated osteoclast-specific p130Cas conditional knockout (p130CasOCL-) mice. p130CasOCL- mice exhibit a high bone mass phenotype caused by defect in multinucleation and cytoskeleton organization causing bone resorption deficiency. Bone marrow cells from p130CasOCL- mice were able to differentiate into osteoclasts in vitro. However, osteoclasts from p130CasOCL- mice failed to form actin rings and resorb pits on dentine slices. Although the initial events of osteoclast attachment, such as ntegrin or Src phosphorylation, were intact, the Rac1 activity that organizes the actin cytoskeleton was reduced, and its distribution was disrupted in p130CasOCL- osteoclasts. Dock5, a Rho family guanine nucleotide exchanger, failed to associate with Src or Pyk2 in osteoclasts in the absence of p130Cas. These results strongly indicate that p130Cas plays pivotal roles in osteoclastic bone resorption.