Osteocyte control of bone remodeling through the PTH receptor

骨细胞通过 PTH 受体控制骨重塑

• 批准号: 8966655
• 负责人: Teresita M. Bellido
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966655
• 关键词: Adult; Aging; Binding; Biology; Bone Resorption; Bone remodeling; Calcium; Calvaria; Cell physiology; Cells; Cholecalciferol; Collagen Type I; Data; Disease; Distal; Enhancers; Excision; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Family; Functional disorder; General Population; Generations; Genes; Goals; Gonadal Steroid Hormones; Health; Homeostasis; Hormones; Human; IL6ST gene; In Vitro; Infusion procedures; Lactation; MMP14 gene; Maintenance; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Membrane; Mission; Modeling; Mus; Mutate; Organ Culture Techniques; Osteoblasts; Osteoclasts; Osteocytes; Osteoporosis; PTH gene; Paralysed; Parathyroid Hormone Receptor; Patients; Population; Positioning Attribute; Public Health; Regulation; Research; Resistance; Secondary to; Signal Transduction; Skeleton; Source; Staging; TNFSF11 gene; Testing; Therapeutic; Up-Regulation; Veterans; Vitamin D3 Receptor; Wild Type Mouse; Work; alternative treatment; base; bone; bone cell; bone mass; collagenase 3; cytokine; effective intervention; hormone deficiency; in vivo; novel; novel therapeutics; osteoclastogenesis; prevent; progenitor; response; skeletal

DESCRIPTION (provided by applicant): Recent studies led by the PI demonstrated that activation of PTH receptor signaling in osteocytes is sufficient to increase bone mass and the rate of remodeling, two recognized actions of PTH on the skeleton; positioning osteocytes as crucial target cells of the hormone. The long term goal of this research is to determine the contribution of osteocytes to the regulation of skeletal homeostasis. The specific goal of this proposal is to reveal the mechanisms by which osteocytes induce bone resorption in response to PTH. Mice treated with PTH or expressing a constitutively active PTH receptor in osteocytes exhibit increased osteoclasts and elevated bone resorption. Conversely, mice lacking the PTH receptor in osteocytes exhibit decreased bone resorption. PTH-induced resorption is due to upregulation of the RANKL gene and requires extracellular matrix degradation by matrix metalloproteinases (MMPs). Although it is recognized that the pro-osteoclastogenic action of PTH is mediated by cells of the osteoblastic lineage, the precise stage of differentiation of the PTH target cell remains unknown. Recent evidence indicates that osteocytes are an important source of RANKL; and that they secrete MMP13, which might facilitate osteoclast recruitment and resorption, and express membrane-bound MMP14 (or MT1-MMP), which remodels the pericellular matrix thus maintaining the osteocyte canalicular network and also induces RANKL shedding. Based on this evidence and findings showing that the expression of RANKL, MMP13 and MMP14 is elevated by activation of PTH receptor signaling in osteocytes, we hypothesize that direct effects of PTH on osteocytes increase RANKL and MMPs, which in turn act as osteocyte-derived factors to increase osteoclast formation and activity, and bone resorption. This hypothesis will be tested by pursuing two specific aims that combine in vivo and in vitro approaches and use novel genetically modified mice and murine and human osteocytic cells and murine primary osteocytes. Aim 1 will examine the contribution of membrane-bound and soluble RANKL to resorption induced by PTHR1 activation in osteocytes. Aim 2 will determine the contribution of osteocyte-derived MMPs to PTH-induced resorption. Successful completion of the proposed studies will positively impact basic bone biology and pathophysiology by advancing our understanding of the mechanisms by which PTH receptor signaling in osteocytes regulates the function of the cells that remodel bone, osteoclasts and osteoblasts, in health and disease.

描述（由申请人提供）： PI 领导的最新研究表明，骨细胞中 PTH 受体信号传导的激活足以增加骨量和重塑率，这是 PTH 对骨骼的两个公认的作用；将骨细胞定位为激素的关键靶细胞。这项研究的长期目标是确定骨细胞对骨骼稳态调节的贡献。该提案的具体目标是揭示骨细胞响应 PTH 诱导骨吸收的机制。用 PTH 治疗或在骨细胞中表达组成型活性 PTH 受体的小鼠表现出破骨细胞增加和骨吸收增加。相反，骨细胞中缺乏 PTH 受体的小鼠表现出骨吸收减少。 PTH 诱导的吸收是由于 RANKL 基因的上调，并且需要基质金属蛋白酶 (MMP) 降解细胞外基质。尽管人们认识到 PTH 的促破骨作用是由成骨细胞谱系的细胞介导的，但 PTH 靶细胞的精确分化阶段仍然未知。最近的证据表明，骨细胞是 RANKL 的重要来源；它们分泌 MMP13，可能促进破骨细胞的募集和吸收，并表达膜结合 MMP14（或 MT1-MMP），重塑细胞周基质，从而维持骨细胞小管网络，并诱导 RANKL 脱落。基于这些证据和研究结果表明，RANKL、MMP13和MMP14的表达通过骨细胞中PTH受体信号传导的激活而升高，我们假设PTH对骨细胞的直接影响增加了RANKL和MMP，而RANKL和MMP反过来又充当骨细胞衍生因子，增加破骨细胞的形成和活性以及骨吸收。这一假设将通过追求两个具体目标来检验，即结合体内和体外方法，并使用新型转基因小鼠、鼠类和人类骨细胞以及鼠类原代骨细胞。目标 1 将检查膜结合和可溶性 RANKL 对骨细胞中 PTHR1 激活诱导的吸收的贡献。目标 2 将确定骨细胞衍生的 MMP 对 PTH 诱导的吸收的贡献。成功完成拟议的研究将通过增进我们对骨细胞中 PTH 受体信号传导调节健康和疾病中重塑骨骼、破骨细胞和成骨细胞的功能的机制的理解，对基础骨生物学和病理生理学产生积极影响。