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)主要被认为是调节哺乳期和社会纽带的，对骨骼是合成代谢的。循环OT降低到野生型小鼠一半的杂合子小鼠没有表现出哺乳缺陷，而是表现出严重的骨量减少和骨形成减少。骨吸收没有受到影响，可能是由于OT对破骨细胞形成和功能的相反作用。总而言之，这些数据表明，OT的成骨作用占主导地位，而且可能比它对乳房的影响更古老。不出所料，OT注射到野生型小鼠体内，通过促进成骨细胞的形成来增加骨量，而在基质细胞培养中，它刺激矿化克隆的形成。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回路可能会潜在地放大注射OT的成骨作用。我们假设OT是一种合成代谢的骨激素，它的作用是通过成骨细胞OXTR介导的，当OT刺激时，OXTR在自分泌环中局部产生OT。在具体目标1中，我们将研究注射OT是否能恢复衰老和性腺功能低下小鼠丢失的骨。在特定的目标2中，我们将通过对OXTR的细胞选择性基因消融来阐明成骨细胞、破骨细胞或两者都参与了OT的作用。在具体目标3中，我们将确定注射OT的成骨作用是否需要骨髓OT使用OT-/-小鼠和骨髓移植。我们的研究应该有助于建立OT和Oxtrs作为治疗人类骨质疏松症的潜在靶点。

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.