Gas-Hedgehog signaling in intramembranous bone formation and expansion

Gas-Hedgehog 信号在膜内骨形成和扩张中的作用

• 批准号: 9977003
• 负责人: Yingzi Yang
• 金额: $ 47.16万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977003
• 关键词: Adult; Affect; Alleles; Biological Process; Bone Development; Bone Diseases; Bone Growth; Cell physiology; Cells; Clinical; Complication; Connective Tissue; Craniofacial Abnormalities; Craniosynostosis; Critical Pathways; Development; Disease; Dysplasia; Embryonic Development; Erinaceidae; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gases; Genes; Genetic; Genetic Diseases; Growth; Heterotopic Ossification; Human; Human Genetics; Joints; Knowledge; Ligands; Light; Maintenance; Malignant Neoplasms; McCune-Albright Syndrome; Mediating; Mesenchymal Stem Cells; Mesenchyme; Molecular; Morphogenesis; Motion; Mutation; Natural regeneration; Online Mendelian Inheritance In Man; Osteoblasts; Osteogenesis; Osteoporosis; Pathologic; Pathway interactions; Patients; Physiologic Ossification; Physiological; Play; Process; Progressive osseous heteroplasia; Proteins; Regulation; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal system; Source; Subcutaneous Tissue; Surgical complication; Surgical sutures; Testing; Tissues; Trauma; Up-Regulation; WNT Signaling Pathway; acquired heterotopic ossification; beta catenin; body system; bone; cell fate specification; cell growth regulation; cell type; chronic pain; craniofacial; craniofacial bone; cranium; human disease; insight; intramembranous bone; intramembranous bone formation; loss of function mutation; mouse model; novel; osteoblast differentiation; osteogenic; rare genetic disorder; recruit; repaired; skeletal; skeletal disorder; smoothened signaling pathway; soft tissue; stem cells

Gαs-Hedgehog signaling in intramembranous bone formation and expansion Summary The development of a functional skeletal system requires tight spatial and temporal control of osteoblast differentiation and maturation. How osteoblast cells are induced at the outset of bone development is a central question in understanding the organizational principles underpinning a functional skeletal system. Extraskeletal or heterotopic ossification (HO) occurs as a common complication of trauma or in rare genetic disorders and can be disabling and lethal. The precise cellular and molecular mechanisms underlying HO are not clear. Research in our lab has provided insights into the molecular and cellular regulation of bone development and recently we have identified a novel Gαs-Hedgehog (Hh) signaling axis that critically regulates ectopic osteoblast differentiation in progressive osseous heteroplasia (POH). POH is a rare human genetic disease in which HO occurs predominantly through an intramembranous process and progresses from subcutaneous tissue into skeletal muscle and deep connective tissues. POH is caused by inactivating mutations in GNAS that encodes Gαs that transduces signals from G protein coupled receptors (GPCRs). We have found that loss of Gαs function in POH leads to ligand-independent activation of Hh signaling, which in turn induces osteoblast differentiation of mesenchyme cells in soft tissues, whereas activation of Gαs signaling leads to Wnt/β-catenin signaling upregulation and reduced osteoblast differentiation in the human condition of fibrous dysplasia (FD). We have further observed in our preliminary studies that ectopic bone formation and expansion in POH bare cellular and molecular similarities to craniofacial bone development. Here we will build upon our unique perspectives and test our central hypothesis: Hh signaling activation by Gαs inhibition induces osteoblast differentiation during intramembranous bone formation and recruits wild type cells into ectopic bone during progressive ossification in POH. In Specific Aim 1, we will investigate the role of Gαs-regulated Hh signaling during formation and growth of intramembranous bone. In Specific Aim 2, we will extend findings in normal craniofacial bone growth to ectopic bone in POH. We will test our hypothesis that ectopic bone in POH expands by inducing a suture-like tissue where wild type osteogenic mesenchyme stem cells reside. Our proposed studies will provide an unprecedented level of insight in acquired HO and the regulation of osteoblast differentiation under both physiological and pathological conditions. Knowledge gained here from the mouse models of POH will be readily translatable to human diseases such as POH, acquired HO, FD, craniosynostosis and osteoporosis. We anticipate that our findings will have broad significance with respect to cell-fate specification and reprogramming processes during development, repair, and regeneration of many other organ systems where Gαs-Hh and Gαs-Wnt signaling plays a critical role and enhance our understanding of these signaling pathways in human diseases including cancer.

G-αS-Hedgehog信号在膜内骨形成和扩张中的作用 摘要 功能骨骼系统的发展需要对成骨细胞进行严格的时空控制。 分化和成熟。成骨细胞是如何在骨骼发育开始时被诱导的是一个中心 在理解支撑起作用的骨架系统的组织原则方面的问题。骨外 或异位骨化(HO)作为创伤或罕见遗传性疾病的常见并发症而发生 可能会致残并致命。HO的确切细胞和分子机制尚不清楚。 我们实验室的研究为骨骼发育的分子和细胞调控提供了洞察力 最近我们发现了一个新的GαS-Hedgehog(HH)信号轴，它关键地调节异位 进行性骨质疏松症(POH)中的成骨细胞分化。POH是一种罕见的人类遗传性疾病 HO主要通过膜内突起发生，并从皮下进展 组织分化为骨骼肌和深层结缔组织。POH是由GNAS中的失活突变引起的 该基因编码G蛋白偶联受体(G-α)信号的S。我们已经找到了这一损失 在POH中GαS功能的缺失导致HH信号的非配体激活，进而诱导成骨细胞 软组织中间充质细胞的分化，而G-αS信号的激活导致Wnt/β-连环蛋白 纤维异常增殖症(FD)患者成骨细胞分化信号上调和减少。 我们在初步研究中进一步观察到POH裸露的异位骨形成和扩张 细胞和分子与头面部骨骼发育的相似性。在这里，我们将建立在我们独特的 透视和检验我们的中心假设：G-α抑制HH信号激活诱导S 成骨细胞在膜内骨形成过程中的分化并将野生型细胞招募到 POH进行性骨化过程中的异位骨。在具体目标1中，我们将调查 GαS调控膜内骨形成和生长过程中的HH信号。在具体目标2中， 我们将把正常颅面骨生长的结果推广到POH的异位骨。我们将测试我们的 POH异位骨通过诱导缝线样组织扩张的假说 成骨间充质干细胞存在。我们建议的研究将提供前所未有的水平 获得性HO的洞察及生理和病理条件下成骨细胞分化的调控 条件。从POH小鼠模型中获得的知识将很容易翻译给人类 POH、获得性HO、FD、颅骨融合、骨质疏松症等疾病。我们预计我们的发现 将对细胞命运指定和重新编程过程具有广泛的意义 许多其他器官系统的发育、修复和再生，其中GαS-HH和GαS-Wnt信号 在人类疾病中扮演着重要的角色，并加深了我们对这些信号通路的了解，包括 癌症。