Nakajima Arata, Sanjay Archana, Chiusaroli Riccardo, Adapala Naga Suresh, Neff Lynn, Itzsteink Cecile, Horne William C, Baron Roland
Department of Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut, USA.
J Bone Miner Res. 2009 Jul;24(7):1162-72. doi: 10.1359/jbmr.090205.
Cbl proteins are multifunctional adaptor molecules that modulate cellular activity by targeting the ubiquitylating system, endocytic complexes, and other effectors to a wide variety of regulatory proteins, especially activated receptor and nonreceptor tyrosine kinases. Cbl and Cbl-b perform unique functions in various cells, in addition to redundant functions that are required for embryonic development. We previously showed that eliminating Cbl impaired osteoclast motility, which modestly delayed embryonic bone development. We now report that Cbl-b(-/-) mice are osteopenic, because of increased bone resorption with little compensating increase in bone formation. In vitro bone-resorbing activity and differentiation of osteoclast-like cells (OCLs) were increased, as were some RANKL-induced signaling events (activation of NF-kappaB and the mitogen-activated protein kinases extracellular signal-regulated kinase [ERK] and p38), suggesting that specific RANKL-activated mechanisms contribute to the increased rate of differentiation and bone-resorbing activity. Re-expressing Cbl-b in Cbl-b(-/-) OCLs normalized the increased bone-resorbing activity and overexpressing Cbl-b in wildtype OCLs inhibited bone resorption. Cbl was without effect in either wildtype or Cbl-b(-/-) OCLs. Functional tyrosine kinase binding (TKB) and RING finger domains were required for the rescue by Cbl-b. Thus, both Cbl and Cbl-b perform regulatory functions in osteoclasts that are unique to one or the other protein (i.e., functions that cannot be compensated by the other homolog). One of Cbl-b's unique functions in osteoclasts is to downregulate bone resorption.
Cbl蛋白是多功能衔接分子，通过将泛素化系统、内吞复合物和其他效应分子靶向多种调节蛋白，特别是活化受体和非受体酪氨酸激酶，来调节细胞活性。除了胚胎发育所需的冗余功能外，Cbl和Cbl-b在各种细胞中发挥独特功能。我们之前发现，敲除Cbl会损害破骨细胞的运动能力，从而适度延迟胚胎骨骼发育。我们现在报告，Cbl-b(-/-)小鼠患有骨质疏松症，原因是骨吸收增加，而骨形成几乎没有相应增加。破骨细胞样细胞（OCLs）的体外骨吸收活性和分化增加，一些RANKL诱导的信号事件（NF-κB、丝裂原活化蛋白激酶细胞外信号调节激酶[ERK]和p38的激活）也增加，这表明特定的RANKL激活机制导致分化率和骨吸收活性增加。在Cbl-b(-/-) OCLs中重新表达Cbl-b可使增加的骨吸收活性恢复正常，而在野生型OCLs中过表达Cbl-b则抑制骨吸收。Cbl对野生型或Cbl-b(-/-) OCLs均无影响。Cbl-b的拯救作用需要功能性酪氨酸激酶结合（TKB）和RING指结构域。因此，Cbl和Cbl-b在破骨细胞中都发挥着独特的调节功能（即一种蛋白的功能不能被另一种同源蛋白补偿）。Cbl-b在破骨细胞中的独特功能之一是下调骨吸收。
