Vav3 regulates osteoclast function and bone mass
Vav3 regulates osteoclast function and bone mass
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DOI：
10.1038/nm1194
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发表时间：
2005-03-01
期刊：
影响因子：
82.9
通讯作者：
Swat, W
中科院分区：
文献类型：
--
作者：
Faccio, R;Teitelbaum, SL;Swat, W
骨质疏松症是老年人发病的主要原因，其特征是由于相对于成骨细胞骨形成的过量骨吸收导致的骨量进行性丢失。在这里，我们确定Vav 3，Rho家族的鸟嘌呤核苷酸交换因子，刺激破骨细胞活化和骨密度在体内是必不可少的。Vav 3缺陷型破骨细胞表现出由M-CSF受体和α（v）β（3）整联蛋白下游信号传导受损导致的肌动蛋白细胞骨架组织、极化、扩散和再吸收活性缺陷。Vav 3缺陷型小鼠的骨量增加，并受到保护，免受全身性骨吸收刺激物（如甲状旁腺激素或RANKL）诱导的骨丢失。此外，我们提供的Syk酪氨酸激酶的作用，作为一个重要的上游调节Vav 3在破骨细胞的遗传和生化证据。因此，Vav 3是抗骨质疏松治疗的潜在新靶点。
Osteoporosis, a leading cause of morbidity in the elderly, is characterized by progressive loss of bone mass resulting from excess osteoclastic bone resorption relative to osteoblastic bone formation. Here we identify Vav3, a Rho family guanine nucleotide exchange factor, as essential for stimulated osteoclast activation and bone density in vivo. Vav3-deficient osteoclasts show defective actin cytoskeleton organization, polarization, spreading and resorptive activity resulting from impaired signaling downstream of the M-CSF receptor and alpha(v)beta(3) integrin. Vav3-deficient mice have increased bone mass and are protected from bone loss induced by systemic bone resorption stimuli such as parathyroid hormone or RANKL. Moreover, we provide genetic and biochemical evidence for the role of Syk tyrosine kinase as a crucial upstream regulator of Vav3 in osteoclasts. Thus, Vav3 is a potential new target for antiosteoporosis therapy.