Endocrine Actions of Sclerostin

骨骼由大量的成骨细胞和骨细胞组成，需要持续的 富含能量的分子，为骨形成过程中骨基质的合成、沉积和矿化提供燃料 建模和改造。因此，在过去十年中进行的研究扩大了我们的 了解骨骼的生理功能，超越运动，矿物质离子储存和保护 现在包括有助于调节整个身体的激素分泌 新陈代谢.我们以前的研究表明，硬化素，骨细胞分泌的因子，抑制Wnt 骨信号，通过增加脂肪细胞，影响身体组成和葡萄糖稳态 分化初步研究表明，sclerostin可能通过以下方式对体内脂肪组织发挥作用： 调节脂肪细胞对刺激脂肪组织布朗宁的β-肾上腺素能信号的敏感性。在 在这次更新申请中，我们将利用遗传学和药理学方法的结合来探索 内分泌硬化素和β-肾上腺素能信号之间的相互作用。我们的假设预测， sclerostin缺乏导致脂肪组织布朗宁，这是由于β-肾上腺素能敏感性的增加;和 负反馈抑制的丧失，因为sclerostin基因表达似乎响应于 产热信号我们的方法将扩大我们对生理功能的理解， sclerostin;并帮助确定sclerostin中和，现在批准用于治疗 骨质减少/骨质疏松症，可以用来治疗代谢紊乱，如肥胖和糖尿病。我们坚决 我相信，从我们的研究中获得的信息将有助于理解代谢活动是如何 会影响整体代谢活动这些信息预计将大大改善 糖尿病相关代谢紊乱的诊断、管理、治疗和预防， 老年退伍军人的骨病。

The skeleton, populated by large numbers of osteoblasts and osteocytes, requires a constant supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix during bone modeling and remodeling. As a result, studies performed over the last decade have expanded our understanding of the physiologic functions of bone beyond locomotion, mineral ion storage, and protection of vital organs to now include the secretion of hormones that contribute to the regulation of whole-body metabolism. Our previous studies suggest that sclerostin, an osteocyte-secreted factor that inhibits Wnt signaling in bone, influences body composition and glucose homeostasis by augmenting adipocyte differentiation. Preliminary studies suggest that sclerostin may exert its effect on adipose tissue in vivo by modulating the sensitivity of adipocytes to -adrenergic signals that stimulate adipose tissue browning. In this renewal application, we will utilize a combination of genetic and pharmacological approaches to explore the interaction between endocrine sclerostin and -adrenergic signaling. Our hypothesis predicts that sclerostin deficiency leads to adipose tissue browning due to an increase in -adrenergic sensitivity; and the loss of negative feedback inhibition since sclerostin gene expression appears to be responsive to thermogenic signaling. Our approach will expand our understanding of the physiologic functions of sclerostin; and help to determine if sclerostin neutralization, now approved for the treatment of osteopenia/osteoporosis, can be leveraged to treat metabolic disorders like obesity and diabetes. We firmly believe that the information gained from our studies will improve understanding of how the metabolic activity of the skeleton impacts global metabolic activity. Such information is expected to significantly improve the diagnosis, management, treatment, and prevention of the related metabolic disturbances of diabetes and bone disease in aging Veterans.