Exploring The Posterior Pituitary-Bone Connection

描述（由申请人提供）：我们最近报道，垂体后叶激素催产素（OT）被认为主要是调节哺乳和社会联系，是合成代谢的骨骼。循环OT减少到野生型小鼠一半的杂合子小鼠没有表现出泌乳缺陷，而是表现出严重的骨质减少和骨形成减少。骨吸收未受影响，可能是由于OT对破骨细胞形成和功能的相反作用。总之，这些数据表明，OT的骨形成作用是占主导地位的，也许比它对乳房的影响更古老。预期，OT注射到野生型小鼠通过增强成骨细胞生成来增加骨量，而在基质细胞培养物中，它刺激矿化集落形成。此外，我们最近发现骨髓成骨细胞不仅具有丰富的OT受体（Oxtrs），而且还能产生OT。这意味着骨髓中的自分泌OT回路可能会放大注射OT的骨形成作用。我们假设OT是一种合成代谢性骨激素，其作用是通过成骨细胞Oxtr介导的，当受到OT刺激时，Oxtr在自分泌回路中局部产生OT。在具体目标1中，我们将研究注射OT是否可以恢复衰老和性腺功能减退小鼠中丢失的骨。在具体目标2中，我们将阐明，通过细胞选择性基因消融的Oxtr，是否成骨细胞，破骨细胞或两种细胞参与OT的行动。在具体目标3中，我们将使用OT-/-小鼠和骨髓移植确定骨髓OT是否是注射OT的骨形成作用所必需的。我们的研究将有助于确定OT和Oxtrs作为治疗人类骨质疏松症的潜在靶点。 公共卫生相关性：骨质疏松症影响至少5000万美国人，他们每年遭受约240万次使人衰弱的骨折，导致约180亿美元的总费用。目前的建议支持了我们最近的发现，垂体激素，催产素（OT），调节骨骼的完整性。我们将利用药理学和小鼠遗传学研究的补充，以确定是否OT或其受体可以用来治疗骨质疏松症。

DESCRIPTION (provided by applicant): We reported recently that the posterior pituitary hormone oxytocin (OT) thought primarily to regulate lactation and social bonding is anabolic to the skeleton. Heterozygote mice with circulating OT reduced to half that of wild type mice showed no lactation defect, but instead displayed severe osteopenia and reduced bone formation. Bone resorption remained unaffected, likely due to the opposing actions of OT on osteoclast formation and function. Together the data suggest that the bone forming action of OT is dominant, and perhaps more ancient than its effect on the breast. Expectedly, OT injected into wild type mice increased bone mass by enhancing osteoblastogenesis, whereas in stromal cell cultures, it stimulated mineralized colony formation. Furthermore, we found recently that bone marrow osteoblasts not only possess abundant OT receptors (Oxtrs), but also produce OT. This means that an autocrine OT circuit in marrow could potentially amplify the bone forming action of injected OT. We hypothesize that OT is an anabolic bone hormone, and that its action is mediated through an osteoblast Oxtr, which when stimulated by OT, produces OT locally in an autocrine loop. In Specific Aim 1, we will investigate whether injected OT can restore the lost bone in aging and hypogonadal mice. In Specific Aim 2, we will elucidate, through cell-selective genetic ablation of the Oxtr, whether osteoblasts, osteoclasts or both cells participate in the action of OT. In Specific Aim 3, we will determine whether marrow OT is required for the bone forming action of injected OT using OT-/- mice and bone marrow transplantation. Our studies should help establish OT and Oxtrs as potential targets for treating human osteoporosis. PUBLIC HEALTH RELEVANCE: Osteoporosis affects at least 50 million Americans who suffer from around 2.4 million debilitating fractures each year resulting in an overall expense of ~$18 billion. The present proposal underpins our more recent finding that a pituitary hormone, oxytocin (OT), regulates skeletal integrity. We will utilize a complement of pharmacological and mouse genetic studies to determine whether OT or its receptor can be leveraged to treat osteoporosis.