GPCR kinase 2 interacting protein 1 (GIT1) regulates osteoclast function and bone mass.
GPCR kinase 2 interacting protein 1 (GIT1) regulates osteoclast function and bone mass.
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DOI：
10.1002/jcp.22282
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发表时间：
2010-11
影响因子：
5.6
通讯作者：
Berk, Bradford C.
中科院分区：
文献类型：
--
作者：
Menon, Prashanthi;Yin, Guoyong;Smolock, Elaine M.;Zuscik, Michael J.;Yan, Chen;Berk, Bradford C.
g蛋白偶联受体（GPCR）激酶2相互作用蛋白-1 （GIT1）是多种细胞类型中表达的支架蛋白，包括神经元、内皮细胞和血管平滑肌细胞。GIT1敲除（KO）小鼠由于内皮功能受损而具有肺表型。由于GIT1被Src激酶酪氨酸磷酸化，我们预计GIT1 KO应该具有与Src KO相似的骨表型。长骨的微电脑断层扫描显示，与野生型对照相比，GIT1 KO小鼠骨量增加了2.3倍。组织形态测量显示骨小梁数量和连通性增加，表明骨重塑受损。免疫印迹分析显示，GIT1在破骨细胞和成骨细胞中均有表达。碱性磷酸酶测定成骨细胞活性和功能，矿物结节形成和体内钙黄蛋白标记在GIT1 KO小鼠中正常，表明观察到的骨量增加是由于破骨细胞缺陷所致。GIT1 KO骨髓细胞分化为多核破骨细胞，但在牙本质切片上的骨吸收功能存在缺陷。免疫荧光分析表明，这种缺陷可能是由于足小体带缺失引起的，而先前的研究表明，GIT1是足小体形成所必需的。此外，我们发现GIT1是NFκB （RANK）信号的受体激活因子的调节剂，因为它以Src依赖的方式被酪氨酸磷酸化，并且是磷脂酶C-γ2磷酸化所必需的。这些数据表明，GIT1通过调节破骨细胞功能，在体内是骨量的关键调节因子，提示GIT1是骨质疏松症治疗的潜在靶点。
G-protein coupled receptor (GPCR) kinase 2 interacting protein-1 (GIT1) is a scaffold protein expressed in various cell types including neurons, endothelial and vascular smooth muscle cells. The GIT1 knockout (KO) mouse has a pulmonary phenotype due to impaired endothelial function. Because GIT1 is tyrosine phosphorylated by Src kinase, we anticipated that GIT1 KO should have a bone phenotype similar to Src KO. Microcomputed tomography of the long bones revealed that GIT1 KO mice have a 2.3-fold increase in bone mass compared to wild-type controls. Histomorphometry showed increased trabecular number and connectivity suggesting impaired bone remodeling. Immunoblot analysis of GIT1 expression showed that it was expressed in both osteoclasts and osteoblasts. Osteoblast activity and function assayed by alkaline phosphatase, mineral nodule formation and in vivo calcein labeling were normal in GIT1 KO mice suggesting that the observed increase in bone mass was due to an osteoclast defect. GIT1 KO bone marrow cells differentiated into multinucleated osteoclasts, but had defective bone resorbing function on dentin slices. This defect was likely caused by loss of podosome belt based on immunofluorescence analysis and previous studies showing that GIT1 is required for podosome formation. Furthermore, we found that GIT1 was a regulator of Receptor activator of NFκB (RANK) signaling since it was tyrosine phosphorylated in a Src dependent manner and was required for phospholipase C-γ2 phosphorylation. These data show that GIT1 is a key regulator of bone mass in vivo by regulating osteoclast function, and suggest GIT1 as a potential target for osteoporosis therapy.
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影响因子：
5.3
作者：
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通讯作者：
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DOI：
10.1073/pnas.0502562102
发表时间：
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DOI：
10.1073/pnas.90.10.4485
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