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

基本信息

批准号：
10577758
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
项目类别：
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/10577758
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 Deterioration 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 Maintenance Malignant Neoplasms Mature Bone Mechanical Stress Modeling Molecular Morbidity - disease rate Mus Osteoblasts Osteocytes Osteogenesis Ovariectomy Pathway interactions Physiology Postmenopausal Osteoporosis 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 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 pharmacologic pre-clinical skeletal treatment duration

项目摘要

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节概括骨细胞死亡是骨骼衰老的标志之一，会导致与年龄相关的骨强度下降以及与年龄相关的骨折的增加。除了衰老之外，许多其他因素也会导致骨细胞死亡，包括卸荷、性激素缺乏、糖皮质激素过多、炎症和骨关节炎。虽然骨细胞作为骨重塑的主要调节者，是维持骨重建的潜在分子机制。人们对骨细胞的活力知之甚少。我们的研究旨在填补有关内源性因素的知识空白维持成人骨骼中的骨细胞活力和骨质量，因为这对于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) 信号传导在维持骨细胞活力和骨骼稳态。在最近的一份出版物中，我们确定了一部小说骨细胞存活所需的 FGFR 信号传导。我们证明了成熟细胞中 FGFR 的条件敲除成骨细胞和骨细胞导致幼年（3周大）小鼠的骨细胞死亡，其次导致骨量增加随着这些小鼠年龄的增长，体重增加。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）小鼠的骨细胞可以绕过对正在发育或活跃生长的骨骼的任何影响。这也几周后导致骨细胞死亡，几个月后骨量增加。这些观察结果构成了我们假设的基础，即在成熟的成人骨骼中，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腔隙小管是否重塑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骨细胞活力是否需要细胞自主地 FGFR 信号通路。我们的初步数据还表明了潜在的临床相关情况，无论是增益还是损失—— FGFR 信号在骨中的功能。 FDA 批准的两种 FGFR 抑制剂（Erdafitinib、Pemigatinib）的中位值癌症治疗期为5个月。我们的研究表明，长期使用 FGFR 抑制剂治疗可能会影响骨稳态。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骼特性。最后，我们将确定 FGFR 信号传导是否激活成熟的成骨细胞和骨细胞在促进骨细胞死亡的条件下具有保护作用。这些研究的完成将确定 FGFR 信号传导在维持成人骨细胞活力和骨稳态，他们将评估潜在的不利影响 FGFR 对骨骼的抑制作用，并将识别可用于促进骨骼稳态的新基因。