Loss of Cbl-b Increases Osteoclast Bone-Resorbing Activity and Induces Osteopenia
Loss of Cbl-b Increases Osteoclast Bone-Resorbing Activity and Induces Osteopenia
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DOI：
10.1359/jbmr.090205
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发表时间：
2009-07-01
影响因子：
6.2
通讯作者：
Baron, Roland
中科院分区：
文献类型：
--
作者：
Nakajima, Arata;Sanjay, Archana;Baron, Roland
Cbl蛋白是一种多功能的适配分子，通过靶向泛素化系统、内吞复合物和其他多种调节蛋白的效应物来调节细胞活性，特别是激活的受体和非受体酪氨酸激酶。除了胚胎发育所需的冗余功能外，Cbl和Cbl-b在各种细胞中发挥着独特的功能。我们之前的研究表明，消除Cbl会损害破骨细胞的运动，从而适度延缓胚胎骨的发育。我们现在报道，cb -b（-/-）小鼠骨质减少，因为骨吸收增加，骨形成几乎没有补偿增加。体外破骨细胞样细胞（OCLs）的骨吸收活性和分化增加，一些rankl诱导的信号事件（NF-kappa B和丝裂原激活的蛋白激酶细胞外信号调节激酶[ERK]和p38的激活）也增加，表明特定的rankl激活机制有助于提高分化率和骨吸收活性。在cl -b（-/-）型骨细胞中再表达cl -b使骨吸收活性增加正常化，而在野生型骨细胞中过表达cl -b抑制骨吸收。Cbl对野生型或Cbl-b(-/-) ocl均无影响。功能性酪氨酸激酶结合（TKB）和环指结构域是Cbl-b拯救的必要条件。因此，Cbl和Cbl-b都在破骨细胞中发挥着一种或另一种蛋白质所特有的调节功能（即，不能被另一种同源物补偿的功能）。Cbl-b在破骨细胞中的独特功能之一是下调骨吸收。[J]中华骨科学杂志，2009;24(4):1172 -1172。2009年2月16日在线发布；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-kappa B 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 wildlype 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. J Bone Miner Res 2009;24:1162-1172. Published online on February 16, 2009; doi: 10.1359/JBMR.090205