Exploring The Posterior Pituitary-Bone Connection

描述（由申请人提供）：我们最近报道了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，是骨骼的合成代谢。循环OT减少到野生型小鼠一半的杂合子小鼠没有泌乳缺陷，但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。综上所述，这些数据表明，骨形成的作用是主要的，也许比它对乳房的影响更古老。可想而知，注射到野生型小鼠体内的OT通过促进成骨细胞的形成而增加了骨量，而在基质细胞培养中，OT则刺激了矿化集落的形成。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回路可能潜在地增强注射OT的成骨作用。我们假设OT是一种合成代谢骨激素，其作用是通过成骨细胞Oxtr介导的，当受到OT刺激时，Oxtr在自分泌循环中局部产生OT。在Specific Aim 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Specific Aim 2中，我们将通过细胞选择性基因消融Oxtr来阐明成骨细胞、破骨细胞或两者是否参与OT的作用。在Specific Aim 3中，我们将使用OT-/-小鼠和骨髓移植来确定骨髓OT是否需要骨髓OT来实现注射OT的骨形成作用。我们的研究应该有助于确立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.