Exploring The Posterior Pituitary-Bone Connection

探索垂体后叶与骨的连接

基本信息

批准号：
8316115
负责人：
Mone Zaidi
金额：
$ 38.29万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316115
关键词：
Ablation Acute Affect Aging American Atosiban Biological Assay Bone Marrow Bone Marrow Transplantation Bone Resorption Bone remodeling Breast Breeding Cell Culture Techniques Cell Differentiation process Cells Complement Data Defect Densitometry Dose Fracture Genetic Goals Heterozygote Hormones Human Hypogonadism Lactation Ligands Marrow Mediating Mus Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Ovariectomy Oxytocin Oxytocin Receptor Phenotype Physiological Pituitary Hormones Posterior Pituitary Gland Posterior Pituitary Hormones Production Regulation Reporting Role Serum Skeleton Social Behavior Stromal Cells Structure Wild Type Mouse Work age related autocrine base bone bone cell bone loss bone mass gain of function in vivo loss of function mutant prevent receptor response skeletal social attachment

Ablation Acute Affect Aging American Atosiban Biological Assay Bone Marrow Bone Marrow Transplantation Bone Resorption Bone remodeling Breast Breeding Cell Culture Techniques Cell Differentiation process Cells Complement Data Defect Densitometry Dose Fracture Genetic Goals Heterozygote Hormones Human Hypogonadism Lactation Ligands Marrow Mediating Mus Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Ovariectomy Oxytocin Oxytocin Receptor Phenotype Physiological Pituitary Hormones Posterior Pituitary Gland Posterior Pituitary Hormones Production Regulation Reporting Role Serum Skeleton Social Behavior Stromal Cells Structure Wild Type Mouse Work age related autocrine base bone bone cell bone loss bone mass gain of function in vivo loss of function mutant prevent receptor response skeletal social attachment

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项目摘要

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.

描述（由申请人提供）：我们最近报道说，垂体激素催产素（OT）主要是为了调节泌乳和社会粘合，这与骨架是合成代谢的。杂合子小鼠的循环OT降低到一半的野生型小鼠没有表现出哺乳缺陷，而是表现出严重的骨质减少症和减少骨形成。骨吸收仍然不受影响，这可能是由于OT对破骨细胞形成和功能的相反作用。数据一起表明，OT的骨骼作用是主导的，也许比其对乳房的影响更古老。预计，注射到野生型小鼠中的OT通过增强成骨细胞生成增加了骨骼质量，而在基质细胞培养物中，它刺激了矿化菌落的形成。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），而且还产生了OT。这意味着骨髓中的自分泌OT电路可能会扩大注射OT的骨骼形成作用。我们假设OT是一种合成代谢的骨骼激素，其作用是通过成骨细胞OXTR介导的，当由OT刺激时，它会在自分泌环中局部产生OT。在特定的目标1中，我们将调查注射的OT是否可以恢复衰老和性降压小鼠中损失的骨骼。在特定的目标2中，我们将通过OXTR的细胞选择性遗传消融阐明，无论是成骨细胞，成骨细胞还是两个细胞都参与OT的作用。在特定的目标3中，我们将确定使用OT - / - / - / - 小鼠和骨髓移植的OT形成骨骼作用是否需要骨髓。我们的研究应有助于建立OT和OXTRS作为治疗人骨质疏松症的潜在靶标。