Loss of Cbl-PI3K interaction modulates the periosteal response to fracture by enhancing osteogenic commitment and differentiation.
Loss of Cbl-PI3K interaction modulates the periosteal response to fracture by enhancing osteogenic commitment and differentiation.
复制标题
DOI：
10.1016/j.bone.2016.11.020
复制
发表时间：
2017-03
期刊：
影响因子：
4.1
通讯作者：
Sanjay A
中科院分区：
文献类型：
--
作者：
Scanlon V;Walia B;Yu J;Hansen M;Drissi H;Maye P;Sanjay A
骨膜含有促进骨修复的多能骨祖细胞。调控骨膜细胞对骨折反应的信号通路在很大程度上是未知的。磷脂酰肌醇-3激酶（PI3K）是一种重要的脂质激酶，是调节成骨细胞分化的几个因子的主要下游信号蛋白。Cbl是E3泛素连接酶，是结合p85调控亚基并调节PI3K活性的主要衔接蛋白。酪氨酸737取代Cbl中的苯丙氨酸（Y737F）消除了Cbl与p85亚基之间的相互作用，而不影响Cbl的泛素连接酶功能。在这里，我们使用OsterixRFP报告小鼠研究了PI3K信号在骨折愈合的早期阶段的作用。我们发现，Cbl对PI3K的调节缺失导致骨膜增厚，骨膜细胞增殖增加。虽然骨膜祖细胞分化为软骨细胞和脂肪细胞的多能性没有改变，但在缺乏cl - pi3k相互作用的情况下，成骨分化得到了高度增强。在缺乏ccl - pi3k相互作用的骨膜细胞中观察到的Osterix的稳定性和核定位的增加可能解释了这种增强的成骨分化，因为Osterix转录靶基因（包括骨钙素和BSP）的表达在YF细胞中增加。总的来说，我们的研究结果强调了Cbl和PI3K在骨折修复早期阶段调节骨膜细胞成骨反应中迄今未被探索的新作用。
The periosteum contains multipotent skeletal progenitors that contribute to bone repair. The signaling pathways regulating the response of periosteal cells to fracture are largely unknown. Phosphatidylinositol-3 Kinase (PI3K), a prominent lipid kinase, is a major signaling protein downstream of several factors that regulate osteoblast differentiation. Cbl is an E3 ubiquitin ligase and a major adaptor protein that binds to the p85 regulatory subunit and modulates PI3K activity. Substitution of tyrosine 737 to phenylalanine (Y737F) in Cbl abolishes the interaction between Cbl and the p85 subunit without affecting the Cbl’s ubiquitin ligase function. Here, we investigated the role of PI3K signaling during the very early stages of fracture healing using OsterixRFP reporter mice. We found that the absence of PI3K regulation by Cbl resulted in robust periosteal thickening, with increased proliferation of periosteal cells. While the multipotent properties of periosteal progenitors to differentiate into chondrocytes and adipocytes did not change, osteogenic differentiation in the absence of Cbl-PI3K interaction was highly augmented. The increased stability and nuclear localization of Osterix observed in periosteal cells lacking Cbl-PI3K interaction may explain this enhanced osteogenic differentiation since the expression of Osterix transcriptional target genes including osteocalcin and BSP are increased in YF cells. Overall, our findings highlight a hitherto unexplored and novel role for Cbl and PI3K in modulating the osteogenic response of periosteal cells during the early stages of fracture repair.
登录
查看更多内容
影响因子：
4.6
作者：
Guntur, Anyonya R.;Reinhold, Martina I.;Naski, Michael C.
通讯作者：
Naski, Michael C.
DOI：
10.1152/ajpendo.00791.2007
发表时间：
2008-04-01
影响因子：
5.1
作者：
Dufour, Cecilie;Holy, Xavier;Marie, Pierre J.
通讯作者：
Marie, Pierre J.
影响因子：
4.8
作者：
Grey, A;Chen, Q;Cornish, J
通讯作者：
Cornish, J
影响因子：
8
作者：
Feshchenko, EA;Shore, SK;Tsygankov, AY
通讯作者：
Tsygankov, AY
影响因子：
64.8
作者：
Chan, Charles K. F.;Chen, Ching-Cheng;Luppen, Cynthia A.;Kim, Jae-Beom;DeBoer, Anthony T.;Wei, Kevin;Helms, Jill A.;Kuo, Calvin J.;Kraft, Daniel L.;Weissman, Irving L.
通讯作者：
Weissman, Irving L.