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控 摘要 骨细胞死亡是骨骼老化的标志之一，也是与年龄相关的骨强度下降的原因之一。 以及与年龄相关的骨折的增加。除了衰老，许多其他因素也会导致骨细胞死亡， 包括脱脂、性激素缺乏、糖皮质激素过多、炎症和骨关节炎。虽然 骨细胞是骨重建的主要调节者，骨重建是维持骨重建的基本分子机制。 人们对骨细胞的活性知之甚少。我们的研究旨在填补关于内生因素的知识空白 保持成人骨骼中的骨细胞活性和骨质量，因为这对保持骨骼健康至关重要。 这项建议研究了成纤维细胞生长因子受体(FGFR)信号在血管内皮细胞生长中的新作用。 维持骨细胞活性和骨骼动态平衡。在最近的一份出版物中，我们确定了一部小说 骨细胞存活对FGFR信号的要求。我们发现在成熟的人中有条件地敲除FGFRs 成骨细胞和骨细胞导致幼年(3周龄)小鼠骨细胞死亡，继而骨量增加 随着这些小鼠年龄的增长，这些小鼠的体重。在一项初步的后续研究中，我们暂时灭活了成骨细胞和 成年(12周大)小鼠体内的骨细胞可以绕过对发育或活跃生长的骨骼的任何影响。这也是 导致几周后骨细胞死亡，几个月后骨量增加。这些 观察结果形成了我们的假设的基础，即在成熟的成人骨骼中，FGFR信号是必需的 维持骨细胞活性和骨内环境平衡。 我们建议的研究将解决FGFR信号维持骨细胞活性的机制 和成年小鼠的骨骼动态平衡。使用血统追踪和合成代谢负荷，我们将确定 现有的骨细胞与新生的骨细胞对FGFR信号的丢失很敏感。体内分析将 确定细胞死亡的主要方式，并确定骨细胞腔隙管的重塑 系统是骨细胞活力丧失的原因或结果。骨细胞系Will的体外分析 确定FGFR信号通路是否是细胞自主地维持骨细胞活性所必需的。 我们的初步数据也暗示了潜在的临床相关情况，无论是得失 FGFR信号在骨中的作用。FDA批准的两种FGFR抑制剂(Erdafitinib，Pemigatinib)的中位数 癌症的疗程为5个月。我们的研究表明，长期使用FGFR抑制剂治疗 会影响骨骼的动态平衡。因此，我们将测试Erdafitinib对骨细胞活性和生物力学的影响 成年和老年小鼠骨骼的特性。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具有保护作用。 这些研究的完成将确立FGFR信号转导在 维持成人骨细胞活性和骨稳态，他们将评估潜在的不良影响 我们将研究FGFR对骨骼的抑制作用，并将确定可能针对促进骨骼动态平衡的新基因。

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.