Endocrine Actions of Sclerostin

骨骼由大量的成骨细胞和骨细胞组成，需要持续供应 能量丰富的分子促进骨基质的合成、沉积和矿化 造型和改建。因此，在过去十年中进行的研究扩大了我们的 了解骨骼的运动、矿物质离子储存和保护以外的生理功能 现在包括有助于调节全身的荷尔蒙的分泌 新陈代谢。我们之前的研究表明，硬化素是一种抑制WNT的骨细胞分泌因子 骨骼中的信号，通过增加脂肪细胞来影响身体成分和血糖稳态 差异化。初步研究表明，硬化素可能通过以下途径对体内脂肪组织发挥作用 调节脂肪细胞对刺激脂肪组织褐变的-肾上腺素能信号的敏感性。在……里面 本次续展申请，我们将利用遗传学和药理学相结合的方法探索 内分泌硬化素与-肾上腺素能信号的相互作用我们的假设预测 由于-肾上腺素能敏感度的增加，硬化素缺乏导致脂肪组织褐变； 失去负反馈抑制，因为硬化素基因表达似乎对 生热信号。我们的方法将扩大我们对心脏的生理功能的理解 并帮助确定硬化素中和，现在被批准用于治疗 骨量减少/骨质疏松症，可用于治疗肥胖和糖尿病等代谢紊乱。我们坚定地 相信从我们的研究中获得的信息将提高对新陈代谢活动如何 骨骼的变化影响全球新陈代谢活动。这些信息预计将显著改善 糖尿病和糖尿病相关代谢紊乱的诊断、管理、治疗和预防 老年退伍军人中的骨病。

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.