The impact of age-related changes in osteoclast function on the skeleton (R01)

年龄相关的破骨细胞功能变化对骨骼的影响（R01）

• 批准号: 10210521
• 负责人: Megan M Weivoda
• 金额: $ 49.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2021-12-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210521
• 关键词: Adult; Affect; Age; Age-Related Bone Loss; Aging; American; Area; Behavior; Behavioral; Bone Diseases; Bone Resorption; Calvaria; Cells; Clinical; Coculture Techniques; Coupled; Coupling; Data; Disease; Embryo; Endopeptidase K; Exhibits; Feedback; Fracture; Giant Cells; Hematopoietic stem cells; Heterogeneity; Human; Impairment; In Vitro; Individual; Link; Longevity; Mediating; Microscopy; Modeling; Mus; Myelogenous; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Peptide Hydrolases; Play; Population; Reporter; Reporting; Risk; Role; Site; Skeleton; Technology; Testing; Time; Transforming Growth Factor beta; Transgenic Mice; Transplantation; Wild Type Mouse; age related; bone; bone erosion; bone loss; bone mass; bone preservation; cathepsin K; fracture risk; improved; in vivo; innovation; insight; interest; mouse model; new therapeutic target; novel; novel therapeutics; osteoporosis with pathological fracture; osteoprogenitor cell; prevent; progenitor; recruit; spine bone structure; tool

Abstract Age-related bone loss puts individuals at risk for debilitating osteoporotic fractures. Current osteoporosis therapies primarily target bone-resorbing osteoclasts to prevent further bone loss; however, because of the coupling of osteoclasts and osteoblasts, these therapies are limited by a concomitant decrease in bone formation. Thus, new treatments are needed to reduce bone loss while protecting or stimulating new bone formation. Osteoclasts are multinucleated cells derived from the myeloid lineage. While most well-known for bone resorption, osteoclasts exhibit a range of functions, including stimulating bone formation by osteoblasts (coupling activity). Increasing evidence shows that osteoclasts exhibit functional heterogeneity. Our data presented herein confirm that not all osteoclasts are actively resorbing or coupling, and others have documented heterogeneity in osteoclast resorptive activity itself. With aging, there is a shift in osteoclast functional distribution, with an increase in the percentage of actively resorbing osteoclasts and a decrease in osteoclasts positive for coupling factor expression. Aging also leads to an increase in an aggressive subpopulation of osteoclasts, which move while resorbing bone leading to trench formation. Our data support that these aggressive, trench-forming osteoclasts, which exhibit greater acidification of the resorption lacunae and increased protease activity, have impaired ability to recruit osteoprogenitors to sites of resorption. Therefore, we hypothesize that the increase in aggressive, trench-forming osteoclasts with age is linked to reduced osteoclast coupling activity, leading to overall bone loss. To test this hypothesis, we propose to 1) Determine whether inducible activation of osteoclast coupling activity prevents age-related bone loss.; 2) Evaluate whether differential osteoclast resorptive behaviors impact coupling; and 3) Test the role of matrix-derived TGF-β as a feedback mechanism to modulate osteoclast activity. Altogether, these studies will reveal the distribution of osteoclast behaviors and how these are dysregulated during aging. In addition, understanding the mechanisms by which changes in resorption contribute to altered coupling activity will reveal potential new therapeutic targets for shifting osteoclast activities to treat osteoclast-mediated bone disease.

抽象的 与年龄相关的骨质流失使人面临骨质疏松性骨折的风险。目前骨质疏松症 治疗主要针对骨吸收破骨细胞，以防止进一步的骨质流失；然而，由于 破骨细胞和成骨细胞的偶联，这些疗法受到骨量减少的限制 形成。因此，需要新的治疗方法来减少骨质流失，同时保护或刺激新骨 形成。破骨细胞是源自骨髓谱系的多核细胞。虽然最出名的是 骨吸收，破骨细胞表现出一系列功能，包括刺激成骨细胞形成骨 （耦合活动）。越来越多的证据表明破骨细胞表现出功能异质性。我们的数据 本文提出的证实并非所有破骨细胞都在主动吸收或偶联，并且其他人已经记录 破骨细胞再吸收活性本身的异质性。随着年龄的增长，破骨细胞的功能分布发生变化， 随着主动吸收破骨细胞百分比的增加和破骨细胞阳性的减少 耦合因子表达。衰老还会导致具有攻击性的破骨细胞亚群增加，从而 骨吸收时移动，导致沟槽形成。我们的数据支持这些侵略性的、形成沟槽的 破骨细胞表现出吸收腔隙更大的酸化和蛋白酶活性增加， 将骨祖细胞募集到吸收部位的能力受损。因此，我们假设增加 随着年龄的增长，具有攻击性、形成沟槽的破骨细胞与破骨细胞偶联活性降低有关，从而导致 整体骨质流失。为了检验这一假设，我们建议 1) 确定破骨细胞是否可诱导激活 耦合活性可防止与年龄相关的骨质流失。 2) 评价破骨细胞是否具有分化吸收能力 行为影响耦合； 3) 测试基质衍生的 TGF-β 作为反馈机制的作用 调节破骨细胞活性。总而言之，这些研究将揭示破骨细胞行为的分布和 这些在衰老过程中如何失调。此外，了解变化的机制 吸收导致耦合活性改变将揭示破骨细胞转移的潜在新治疗靶点 治疗破骨细胞介导的骨病的活动。