Regulation of Osteocyte Survival by Fibroblast Growth Factor Signaling Pathways

成纤维细胞生长因子信号通路对骨细胞存活的调节

• 批准号: 10391803
• 负责人: David M Ornitz
• 金额: $ 52.41万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-21 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391803
• 关键词: Address; Adolescent; Adult; Adverse effects; Affect; Age; Aging; Anoikis; Antineoplastic Agents; Apoptotic; Autophagocytosis; Biological; Biology; Biomechanics; Bone remodeling; Bypass; Cell Death; Cell Line; Cells; Cessation of life; Clinical; Data; Degenerative polyarthritis; Development; Disease; Endogenous Factors; Etiology; FDA approved; FGFR1 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Follow-Up Studies; Fracture; Genes; Glucocorticoids; Gonadal Steroid Hormones; Histologic; Homeostasis; Impairment; In Vitro; Inflammation; Knowledge; Lead; Maintenance; Malignant Neoplasms; Mature Bone; Mechanical Stress; Modeling; Molecular; Morbidity - disease rate; Mus; Osteoblasts; Osteocytes; Osteogenesis; Ovariectomy; Pathway interactions; Pharmacology; Physiology; Postmenopause; Property; Publications; Publishing; Receptor Inhibition; Receptor Signaling; Regulation; Role; Secondary to; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; age related; aged; bone; bone health; bone loss; bone mass; bone quality; bone strength; cancer therapy; clinically relevant; conditional knockout; cost; experimental study; genetic approach; hormone deficiency; in vivo; inhibitor; loss of function; mouse model; novel; pre-clinical; skeletal; treatment duration

Regulation of Osteocyte Survival by Fibroblast Growth Factor Signaling Pathways Summary Osteocyte death, one of the hallmarks of skeletal aging, contributes to the age-related decline in bone strength and the increase in age-related fractures. In addition to aging, many other factors also lead to osteocyte death, including unloading, sex hormone deficiency, glucocorticoid excess, inflammation, and osteoarthritis. Although osteocytes function as master regulators of bone remodeling, the underlying molecular mechanisms that sustain osteocyte viability are poorly understood. Our studies aim to fill a gap in knowledge on endogenous factors that maintain osteocyte viability and bone quality in adult bone, as this is paramount to maintaining bone health. This proposal examines a novel role for Fibroblast Growth Factor Receptor (FGFR) signaling in the maintenance of osteocyte viability and skeletal homeostasis. In a recent publication, we identified a novel requirement for FGFR signaling for osteocyte survival. We showed that conditional knockout of FGFRs in mature osteoblasts and osteocytes led to osteocyte death in juvenile (3-week-old) mice and secondarily, increased bone mass as these mice aged. In a preliminary follow-up study, we temporally inactivated FGFRs in osteoblasts and osteocytes in adult (12-week-old) mice to bypass any effects on developing or actively growing bone. This also resulted in osteocyte death after several weeks and increased bone mass after several months. These observations form the basis of our hypothesis that in mature adult bone, FGFR signaling is required for maintaining osteocyte viability and bone homeostasis. Our proposed studies will address the mechanisms by which FGFR signaling maintains osteocyte viability and skeletal homeostasis in adult mice. Using lineage tracing and anabolic loading we will determine whether existing osteocytes vs newly formed osteocytes are sensitive to loss of FGFR signaling. In vivo analysis will identify the primary mode of cell death and determine whether remodeling of the osteocyte lacunocanalicular system is a cause or a consequence of loss of osteocyte viability. In vitro analysis of osteocyte cell lines will determine if FGFR signaling pathways are required cell-autonomously for osteocyte viability. Our preliminary data also suggests potential clinically relevant circumstances for either gain- or loss-of- function of FGFR signaling in bone. Two FDA approved FGFR inhibitors (Erdafitinib, Pemigatinib) have a median treatment period of 5 months for cancer. Our studies suggest that prolonged treatment with FGFR inhibitors could affect bone homeostasis. We will thus test the effects of Erdafitinib on osteocyte viability and biomechanical properties of bone in adult and aged mice. Finally, we will determine whether activation of FGFR signaling in mature osteoblasts and osteocytes is protective under conditions that promote osteocyte death. Completion of these studies will establish a role and identify mechanisms for FGFR signaling in the maintenance of osteocyte viability and bone homeostasis in adults, they will evaluate potential adverse effects of FGFR inhibition on bone, and will identify new genes that could be targeted to promote skeletal homeostasis.

成纤维细胞生长因子信号通路对骨细胞存活的调控 总结 骨细胞死亡是骨骼衰老的标志之一，它导致了与年龄相关的骨强度下降 以及与年龄有关的骨折的增加。除了衰老，许多其他因素也会导致骨细胞死亡， 包括卸载、性激素缺乏、糖皮质激素过量、炎症和骨关节炎。虽然 骨细胞作为骨重建的主要调节者发挥作用， 对骨细胞活力知之甚少。我们的研究旨在填补对内生因素的知识空白， 维持成人骨中骨细胞的活力和骨质量，因为这对维持骨骼健康至关重要。 该提案研究了成纤维细胞生长因子受体（FGFR）信号转导在细胞凋亡中的新作用。 维持骨细胞活力和骨骼稳态。在最近的一份出版物中，我们发现了一本小说 骨细胞存活的FGFR信号传导的需要。我们发现，在成熟细胞中有条件地敲除FGFR， 成骨细胞和骨细胞导致幼年（3周龄）小鼠的骨细胞死亡，其次是骨增加 随着这些老鼠的年龄增长。在一项初步的后续研究中，我们暂时灭活了成骨细胞中的FGFR， 成年（12周龄）小鼠中的骨细胞，以绕过对发育或活跃生长的骨的任何影响。这也 几周后导致骨细胞死亡，几个月后骨质增加。这些 这些观察形成了我们假设的基础，即在成熟的成人骨中，FGFR信号传导是 维持骨细胞活力和骨稳态。 我们提出的研究将解决FGFR信号维持骨细胞活力的机制 和成年小鼠的骨骼稳态。使用谱系追踪和合成代谢负荷，我们将确定是否 现有的骨细胞与新形成的骨细胞对FGFR信号传导的丧失敏感。体内分析将 确定细胞死亡的主要模式，并确定骨细胞的腔隙性小管重塑是否 系统是骨细胞活力丧失的原因或结果。骨细胞系的体外分析将 确定FGFR信号通路是否是骨细胞活力所需的细胞自主性。 我们的初步数据还表明，无论是获得或损失的潜在临床相关的情况下， FGFR信号在骨中的功能。两种FDA批准的FGFR抑制剂（Erdafitinib，Pemigatinib）的中位 癌症的治疗期为5个月。我们的研究表明，长期使用FGFR抑制剂治疗 会影响骨骼的稳态因此，我们将测试Erdafitinib对骨细胞活力和生物力学的影响。 成年和老年小鼠的骨特性。最后，我们将确定FGFR信号的激活是否在 成熟的成骨细胞和骨细胞在促进骨细胞死亡的条件下是保护性的。 这些研究的完成将确立FGFR信号传导在肿瘤发生中的作用并确定其机制。 维持成人骨细胞活力和骨稳态，他们将评估潜在的不良反应 FGFR抑制对骨的作用，并将确定新的基因，可以有针对性地促进骨骼稳态。