Sclerostin and Gsalpha signaling in osteoblasts

成骨细胞中的硬化蛋白和 Gsalpha 信号传导

• 批准号: 8120592
• 负责人: JOY Y WU
• 金额: $ 7.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120592
• 关键词: Ablation; Age; Aging; American; Anabolic Agents; Attenuated; Birth; Bone Marrow; Bone Resorption; Calvaria; Childhood; Degenerative Disorder; Development; Disease; Elderly; Embryo; Employee Strikes; Fracture; Grant; Harvest; Heterotrimeric GTP-Binding Proteins; Hip Fractures; Homeostasis; Hormones; Image; Limb structure; Longevity; Malignant Neoplasms; Mediating; Mediator of activation protein; Mesenchymal; Molecular; Mus; Osteoblasts; Osteogenesis; Osteopenia; Osteoporosis; Parathyroid Hormone Receptor; Parathyroid gland; Pathway interactions; Patients; Population; Process; Recombinants; Recovery; Relative (related person); Role; Signal Pathway; Signal Transduction; Skeletal Development; Stromal Cells; Teriparatide; Testing; Up-Regulation; Work; bone mass; cost; human PTH protein; inhibitor/antagonist; insight; mortality; novel; osteoblast differentiation; osteogenic; osteoporosis with pathological fracture; osteoprogenitor cell; postnatal; progenitor; public health relevance; skeletal

DESCRIPTION (provided by applicant): Project Summary Osteoporosis, a degenerative disease resulting from an imbalance of bone formation relative to bone resorption, will strike an estimated 50% of Americans over the age of 50. Although fractures call forth images from childhood of a limb in a cast, soliciting autographs and sympathy during a brief period of recovery, fragility fractures in the elderly are far more sinister. The one-year mortality rate for patients over the age of 50 with a hip fracture is an astounding 24%, and only one in three regain their pre-fracture ability to function independently. As lifespans lengthen and the population ages, the costs of osteoporotic fractures - already over $18 billion annually - will surely rise. Current therapies for osteoporosis are mostly anti-resorptive, and therefore not curative. With the recent approval of recombinant human parathyroid hormone (teriparatide, PTH[1-34]), an anabolic agent with potent stimulatory effects on bone formation is now available. However, limitations due to parenteral administration and a potential concern for osteogenic malignancies all point to an enduring need for additional therapies for osteoporosis. The canonical Wnt signaling pathway also has a critical role in bone formation, thus targeting the Wnt pathway is an attractive option for treating osteoporosis. Recent studies have highlighted an important role for sclerostin, an inhibitor of Wnt signaling, and evidence that PTH suppresses sclerostin expression suggests that meaningful cross-talk exists between these two pathways. The heterotrimeric G protein Gs1 is a major downstream mediator of PTH signaling via the PTH/PTH-related peptide receptor. I have found that ablation of Gs1 in the osteoblast lineage in mice (Gs1 KO mice) leads to profound osteoporosis; in these mice sclerostin expression is markedly increased, with a resultant decrease in canonical Wnt signaling. Since the PTH and Wnt pathways likely have both overlapping and distinct actions on bone formation, in this application I propose to determine how inhibition of Wnt signaling by sclerostin contributes to the dramatic reduction of bone mass in Gs1 KO mice. I propose to cross Gs1 KO mice with mice lacking sclerostin (SOST KO mice). In Aim 1 I will examine the role of sclerostin in embryonic skeletal development of Gs1 KO mice. In Aim 2 I will delay ablation of Gs1 in osteoprogenitors until birth, to specifically focus on the function of sclerostin in postnatal skeletal homeostasis. In Aim 3 I will harvest bone marrow stromal cells and calvarial osteoblasts from single and double KO mice to establish how PTH and Wnt signaling pathways interact to regulate mesenchymal lineage commitment and osteogenic differentiation. Understanding the molecular mechanisms underlying the anabolic effects of PTH and Wnt signaling may eventually provide additional targets for the treatment of osteoporosis. PUBLIC HEALTH RELEVANCE: Project Narrative Osteoporosis is a common degenerative disease of aging, and treatments available to cure this debilitating disease are lacking. Parathyroid hormone and the Wnt signaling pathway both act to control bone formation. This proposal seeks to understand how these two pathways interact at the molecular level, as greater insights into the processes by which bone mass is increased may ultimately result in novel therapies for osteoporosis.

描述（由申请人提供）： 项目摘要 骨质疏松症是一种由骨形成与骨吸收不平衡引起的退行性疾病，预计将影响 50% 50 岁以上的美国人。虽然骨折会让人想起童年时肢体打着石膏的样子，在短暂的恢复期间博得亲笔签名和同情，但老年人的脆性骨折要危险得多。 50 岁以上髋部骨折患者的一年死亡率高达 24%，令人震惊，并且只有三分之一的人能够恢复骨折前的独立活动能力。随着寿命的延长和人口老龄化，骨质疏松性骨折的费用（每年已超过 180 亿美元）肯定会上升。目前治疗骨质疏松症的疗法大多是抗骨吸收的，因此不能治愈。随着最近重组人甲状旁腺激素（特立帕肽，PTH[1-34]）的批准，一种对骨形成具有有效刺激作用的合成代谢药物现已上市。然而，肠外给药造成的限制以及对成骨恶性肿瘤的潜在担忧都表明对骨质疏松症额外疗法的持久需求。经典的 Wnt 信号通路在骨形成中也发挥着关键作用，因此靶向 Wnt 通路是治疗骨质疏松症的一个有吸引力的选择。最近的研究强调了硬化素（一种 Wnt 信号传导抑制剂）的重要作用，并且 PTH 抑制硬化素表达的证据表明这两种途径之间存在有意义的串扰。异三聚体 G 蛋白 Gs1 是通过 PTH/PTH 相关肽受体进行 PTH 信号传导的主要下游介质。我发现小鼠成骨细胞谱系中 Gs1 的消融（Gs1 KO 小鼠）会导致严重的骨质疏松症；在这些小鼠中，硬化蛋白表达显着增加，导致经典 Wnt 信号传导减少。由于 PTH 和 Wnt 通路可能对骨形成具有重叠和不同的作用，因此在本申请中，我建议确定硬化素对 Wnt 信号传导的抑制如何导致 Gs1 KO 小鼠骨量的急剧减少。我建议将 Gs1 KO 小鼠与缺乏硬化素的小鼠（SOST KO 小鼠）杂交。在目标 1 中，我将研究硬化素在 Gs1 KO 小鼠胚胎骨骼发育中的作用。在目标 2 中，我将推迟骨祖细胞中 Gs1 的消融直至出生，以特别关注硬化素在产后骨骼稳态中的功能。在目标 3 中，我将从单和双 KO 小鼠中收获骨髓基质细胞和颅骨成骨细胞，以确定 PTH 和 Wnt 信号通路如何相互作用来调节间充质谱系定向和成骨分化。了解 PTH 和 Wnt 信号合成代谢作用背后的分子机制可能最终为骨质疏松症的治疗提供额外的靶点。 公共健康相关性：项目叙述骨质疏松症是一种常见的衰老退行性疾病，目前缺乏治愈这种使人衰弱的疾病的治疗方法。甲状旁腺激素和 Wnt 信号通路均起到控制骨形成的作用。该提案旨在了解这两种途径如何在分子水平上相互作用，因为对骨量增加过程的更深入了解可能最终会产生骨质疏松症的新疗法。