Characterization of a receptor mediating adiponectin functions on bone

 描述（由申请人提供）：近年来，我们一直对最丰富的脂肪因子脂联素的生物学感兴趣。在讨论脂联素在正常饮食动物中的功能时，我们考虑了脂联素在骨的进化过程中出现并受骨源性激素骨钙素调节的事实。然后我们询问脂联素是否调节骨量。体内实验结果表明：1）脂联素通过直接作用于成骨细胞抑制骨形成，而通过脑内信号传导抑制交感神经促进骨形成，2）脂联素的已知受体似乎不介导这两种功能，脂联素不募集AMPK，也不调节成骨细胞中神经酰胺的活性; 3）脂联素在成骨细胞中触发的信号通路提示成骨细胞中脂联素的受体是受体酪氨酸激酶。本申请中提出的进一步分析基于分子和生物化学基础强烈地表明，成骨细胞中以及可能蓝斑神经元中的脂联素受体可能是盘状蛋白受体2（DDR2），其是具有缓慢磷酸化动力学的RTK。基于本申请中提出的初步发现，我们现在提出在体内测试该假设。本申请的具体目的是：证明DDR2介导成骨细胞中的脂联素信号传导。证明体内FoxO 1位于成骨细胞中DDR2依赖性信号的下游。确定DDR2、AdipoR 1和T-cadherin之间相互作用的体内生物学意义。在体内证实DDR2和/或DDR 1介导蓝斑神经元中的脂联素信号传导。

 DESCRIPTION (provided by applicant): We have been interested in recent years in the biology of the most abundant adipokine, adiponectin. In addressing what could be the functions(s) of adiponectin in animals fed a normal diet we considered the fact that adiponectin appears during evolution with bone and is regulated by the bone-derived hormone osteocalcin. We then asked whether adiponectin was regulating bone mass. Our results obtained in vivo showed that 1) adiponectin inhibits bone formation by acting directly on osteoblasts while it favors bone formation by inhibiting the sympathetic nerves through its signaling in the brain; 2) none of the known receptors for adiponectin seem to mediate any of these two functions and adiponectin does not recruit AMPK and does not regulate ceramide activity in osteoblasts; 3) the signaling pathway triggered by adiponectin in osteoblasts suggested that the receptor for this hormone in osteoblasts is a receptor tyrosine kinase. Further analysis presented in this application strongly suggest, based on molecular and biochemical grounds, that the receptor for adiponectin in osteoblasts and possibly in neurons of the locus coeruleus may be the discoidin receptor 2 (DDR2), a RTK with a slow kinetic of phosphorylation. Based on preliminary findings presented in this application we now propose to test this hypothesis in vivo. The specific aims of this application are: To demonstrate that DDR2 mediates adiponectin signaling in osteoblasts. To demonstrate that in vivo FoxO1 lies downstream of DDR2-dependent signaling in osteoblasts. To determine in vivo the biological significance of the interactions occurring between DDR2, AdipoR1 and T-cadherin. To demonstrate in vivo that DDR2 and/or DDR1 mediates adiponectin signaling in neurons of the locus coeruleus.