The mechanistic control of bone quality and joint crosstalk by osteocytes

摘要 骨脆性和关节疾病对老龄人口的骨骼和牙齿健康构成了重大挑战。 然而，这两种疾病都面临着严重的治疗差距。例如，骨脆性疗法治疗低骨症。 质量，但忽略了大约50%的骨折是由骨质质量受损引起的。预防的治疗方法 或者反向关节退行性变仍然难以捉摸。这项研究的长期目标是克服这种治疗方法 GAP通过阐明维持骨骼质量和关节动态平衡的细胞和分子机制。 正在进行的努力强调了骨细胞在这两个过程中的关键作用以及它们对骨骼的贡献。 脆弱和关节疾病。骨细胞在骨骼的动态平衡和疾病中起着重要的作用。 楔周小管重构(PLR)过程。在PLR中，骨细胞分泌酸和蛋白酶以 动态吸收，然后替换周围的骨基质。PLR维持小管网络，并 骨基质材料特性是骨质量的一个主要方面。事实上，转化生长因子β对骨细胞的内在干扰 Tβ缺失/缺失小鼠的信号传递导致股骨作功减少65%至骨折，即使在皮质骨正常的情况下也是如此 质量。初步和新发表的数据记录了人类骨关节炎中PLR的深刻抑制，以及 提供证据表明PLR缺陷在T-β缺失小鼠和小鼠关节退行性变中起致病作用 通过骨细胞内源性消融PLR酶MMP13(MMP13ocy-/-)。此外，PLR被抑制在 骨骼老化的方式与两种小鼠模型大致相同。尽管这些发现表明， 转化生长因子β、MMP13和PLR在增龄性骨质量下降和关节健康中的作用机制 关于PLR在衰老过程中的抑制，或者PLR抑制如何导致骨骼疾病，目前大多尚不清楚。 TβRIIOCY-/-、MMP13OCY-/-和老化骨骼的RNASEQ显示每种模型都有线粒体功能障碍的证据， 这一可能性将在这个项目中进一步探索。将使用一种计算方法来积分 全基因组小鼠RNAseq和人类Gwas数据，以改进对新的、临床相关的识别 与骨骼脆性和骨性关节炎有关的基因。这些结果将优先考虑机械的收益和损失 功能研究验证转化生长因子β依赖的PLR抑制和骨细胞线粒体的假设 功能障碍在与年龄相关的骨骼质量和关节健康下降中起着因果作用。提案将继续执行 三个具体目标：1)确定转化生长因子β和PLR在年龄相关性骨质量和关节丧失中的作用 动态平衡，2)确定与人类骨脆性和关节疾病有关的PLR依赖机制， 3)明确PLR和线粒体功能在衰老过程中的调节机制。这些研究 将揭示PLR在衰老过程中的抑制是否代表了推动暂时性衰退的一种常见细胞机制 骨骼质量和关节健康，此外，如果骨细胞独特的代谢控制创造了机会 专门针对这一细胞群体，以改善衰老过程中的骨骼和牙齿健康。

SUMMARY Bone fragility and joint disease present major challenges to the skeletal and dental health of the aging population. However, both conditions face a serious treatment gap. For example, therapies for bone fragility treat low bone mass, but overlook approximately 50% of fractures that result from impaired bone quality. Therapies to prevent or reverse joint degeneration remain elusive. The long-term goal of this research is to overcome this treatment gap by elucidating the cellular and molecular mechanisms that maintain bone quality and joint homeostasis. Ongoing efforts highlight the critical role of osteocytes in both processes, as well as their contribution to bone fragility and joint disease. Osteocytes play a fundamental role in skeletal homeostasis and disease through the process of perilacunar canalicular remodeling (PLR). In PLR, osteocytes secrete acid and proteases to dynamically resorb, and then replace, the surrounding bone matrix. PLR maintains the canalicular network and bone matrix material properties, a major aspect of bone quality. Indeed, osteocyte-intrinsic disruption of TGFβ signaling in TβRIIocy-/- mice results in a 65% decline in femoral work to fracture, even with normal cortical bone mass. Preliminary and newly published data document profound PLR suppression in human osteoarthritis, and provide evidence that PLR defects play a causal role in joint degeneration in both TβRIIocy-/- mice and in mice with osteocyte-intrinsic ablation of the PLR enzyme MMP13 (MMP13ocy-/-). Furthermore, PLR is suppressed in aging bone in much the same manner as in both mouse models. Although these findings suggest a role for TGFβ, MMP13, and PLR in the age-related decline in bone quality and joint health, the mechanisms responsible for PLR suppression in aging, or by which PLR suppression contributes to skeletal disease are mostly unknown. RNAseq of TβRIIocy-/-, MMP13ocy-/-, and aging bone reveals evidence of mitochondrial dysfunction in each model, a possibility that will be further explored in this project. A computational approach will be used to integrate genome-wide mouse RNAseq and human GWAS data to improve the identification of novel, clinically-relevant genes involved in bone fragility and osteoarthritis. These results will prioritize mechanistic gain and loss of function studies to test the hypothesis that TGFβ-dependent PLR suppression and osteocyte mitochondrial dysfunction play a causal role in the age-related decline in bone quality and joint health. The proposal pursues three specific aims: 1) to determine the role of TGFβ and PLR in age-dependent loss of bone quality and joint homeostasis, 2) to identify PLR-dependent mechanisms implicated in human bone fragility and joint disease, and 3) to identify mechanisms by which PLR and mitochondrial function are deregulated in aging. These studies will reveal if PLR suppression in aging represents a common cellular mechanism that drives the temporal decline of bone quality and joint health, and further, if the unique metabolic control of osteocytes creates opportunities to specifically target this cell population to improve skeletal and dental health in aging.