Loss of Cbl-PI3K interaction in mice prevents significant bone loss following ovariectomy.
Loss of Cbl-PI3K interaction in mice prevents significant bone loss following ovariectomy.
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DOI：
10.1016/j.bone.2014.06.013
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发表时间：
2014-10
期刊：
影响因子：
4.1
通讯作者：
Sanjay, Archana
中科院分区：
文献类型：
--
作者：
Adapala, Naga Suresh;Holland, Danielle;Scanlon, Vanessa;Barbe, Mary F.;Langdon, Wallace Y.;Tsygankov, Alexander Y.;Lorenzo, Joseph A.;Sanjay, Archana
Cbl和Cbl-b是E3泛素连接酶和衔接蛋白，在骨重建中起调节作用。Cbl−/−小鼠由于破骨细胞迁移减少而延迟了骨发育。Cbl-b−/−小鼠由于破骨细胞的骨吸收活性增加而骨质减少。Cbl特有的，但不存在于Cbl-b中的是YEAM基序中的酪氨酸737，其在磷酸化后为PI 3 K的调节性p85亚基提供结合位点。用苯丙氨酸取代酪氨酸737（Y 737 F，CblYF/YF小鼠）防止Y 737磷酸化并消除Cbl-PI 3 K相互作用。我们以前曾报道，CblYF/YF小鼠由于骨吸收缺陷和骨形成增加而增加了骨体积。在这里，我们表明，来自CblYF/YF小鼠的腰椎在卵巢切除术后没有显著的骨丢失。我们的数据还表明，小鼠中Cbl-PI 3 K相互作用的消除导致骨吸收和骨形成之间的偶联的丧失，因为卵巢切除的CblYF/YF小鼠的血清C-末端肽（CTX）水平没有显示出显著变化，而前胶原1型氨基末端前肽（P1 NP）的血清水平降低。相比之下，卵巢切除术后，Cbl−/−和Cbl-b−/−小鼠在胫骨和L2椎骨中显示出显著的骨质丢失，伴随着血清CTX和P1 NP水平的增加。这些数据表明，虽然缺乏Cbl或Cbl-b明显影响骨重建，但只有Cbl-PI 3 K相互作用的丧失保护小鼠免受卵巢切除术后的显著骨丢失。
Cbl and Cbl-b are E3 ubiquitin ligases and adaptor proteins, which perform regulatory roles in bone remodeling. Cbl−/− mice have delayed bone development due to decreased osteoclast migration. Cbl-b−/− mice are osteopenic due to increased bone resorbing activity of osteoclasts. Unique to Cbl, but not present in Cbl-b, is tyrosine 737 in the YEAM motif, which upon phosphorylation provides a binding site for the regulatory p85 subunit of PI3K. Substitution of tyrosine 737 with phenylalanine (Y737F, CblYF/YF mice) prevents Y737 phosphorylation and abrogates the Cbl-PI3K interaction. We have previously reported that CblYF/YF mice had increased bone volume due to defective bone resorption and increased bone formation. Here we show that the lumbar vertebra from CblYF/YF mice did not have significant bone loss following ovariectomy. Our data also suggests that abrogation of Cbl-PI3K interaction in mice results in the loss of coupling between bone resorption and formation, since ovariectomized CblYF/YF mice did not show significant changes in serum levels of c-terminal telopeptide (CTX), whereas the serum levels of pro-collagen type-1 amino-terminal pro-peptide (P1NP) were decreased. In contrast, following ovariectomy, Cbl−/− and Cbl-b−/− mice showed significant bone loss in tibiae and L2 vertebrae, concomitant with increased serum CTX and P1NP levels. These data indicate that while lack of Cbl or Cbl-b distinctly affects bone remodeling, only the loss of Cbl-PI3K interaction protects mice from significant bone loss following ovariectomy.
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