Lowe C, Yoneda T, Boyce B F, Chen H, Mundy G R, Soriano P
Department of Medicine/Endocrinology, University of Texas Health Science Center, San Antonio 78284.
Proc Natl Acad Sci U S A. 1993 May 15;90(10):4485-9. doi: 10.1073/pnas.90.10.4485.
Osteopetrosis is a bone modeling disorder resulting in excessive accumulation of bone matrix due to defective function of osteoclasts, the cells that resorb bone. Mice carrying a targeted disruption of the gene Src that encodes pp60c-src (Src), a nonreceptor protein tyrosine kinase, develop this phenotype but do not exhibit other overt defects despite the fact that the kinase is normally present in a broad variety of cell types. Because Src is expressed in osteoblasts as well as in osteoclasts and both are required for normal bone resorption, the basic defect could occur in either cell type. In this study we have used in vitro approaches and fetal liver transplantation into irradiated Src- recipients to demonstrate that the inherent defect is with osteoclasts and autonomous of the bone marrow microenvironment. This result (i) identifies a cell type in which Src function is essential and cannot be replaced by other related kinases and (ii) should allow the isolation of a substrate that is specific to Src.
骨硬化症是一种骨重塑紊乱疾病，由于破骨细胞（即负责吸收骨的细胞）功能缺陷，导致骨基质过度积累。携带编码pp60c-src（Src）的基因Src靶向破坏的小鼠会出现这种表型，但尽管该激酶通常存在于多种细胞类型中，这些小鼠并未表现出其他明显缺陷。由于Src在成骨细胞和破骨细胞中均有表达，且两者对于正常骨吸收都是必需的，所以基本缺陷可能发生在这两种细胞类型中的任何一种。在本研究中，我们使用体外方法以及将胎肝移植到受照射的Src-受体小鼠体内，以证明内在缺陷在于破骨细胞，且独立于骨髓微环境。这一结果（i）确定了一种细胞类型，其中Src功能至关重要且不能被其他相关激酶替代，（ii）应该有助于分离出Src特异性的底物。
