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

破骨细胞功能与年龄相关的变化对骨骼的影响

• 批准号: 10679050
• 负责人: Megan M Weivoda
• 金额: $ 45.32万
• 依托单位: MAYO CLINIC ROCHESTER
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679050
• 关键词: Adult; Affect; Age; Age-Related Bone Loss; Aging; American; Area; Behavior; Behavioral; Bone Diseases; Bone Formation Stimulation; 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; Transforming Growth Factor beta; Transgenic Mice; Transplantation; Wild Type Mouse; age related; bone; bone erosion; bone loss; bone mass; bone preservation; bone resorbing activity; 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; translation to humans

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.

摘要 与骨质疏松相关的骨质流失使个体处于使人衰弱的骨质疏松性骨折的风险中。当前骨质疏松症 治疗主要靶向骨吸收破骨细胞以防止进一步的骨丢失;然而， 偶联破骨细胞和成骨细胞，这些疗法受到骨密度降低的限制。 阵因此，需要新的治疗方法来减少骨丢失，同时保护或刺激新骨 阵破骨细胞是来源于髓系的多核细胞。虽然最著名的是 骨吸收，破骨细胞表现出一系列的功能，包括刺激骨形成的成骨细胞 （偶联活性）。越来越多的证据表明破骨细胞具有功能异质性。我们的数据 本文所述证实，并非所有破骨细胞都在主动吸收或偶联， 破骨细胞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了变化， 随着主动再吸收破骨细胞百分比的增加， 偶联因子表达衰老还导致破骨细胞的侵袭性亚群增加， 移动，同时吸收骨，导致沟形成。我们的数据支持这些侵略性的， 破骨细胞表现出更强的再吸收陷窝酸化和增加的蛋白酶活性， 将骨祖细胞募集到吸收部位的能力受损。因此，我们假设， 随着年龄的增长，侵袭性的、沟槽形成的破骨细胞与破骨细胞偶联活性的降低有关，导致 整体骨丢失。为了验证这一假设，我们建议：1）确定破骨细胞的诱导激活是否 偶联活动可防止与年龄相关的骨质流失。2)评价是否有差异破骨细胞吸收 行为影响耦合;和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。总之，这些研究将揭示破骨细胞行为的分布， 它们在衰老过程中是如何失调的此外，了解这些变化的机制， 有助于改变偶联活性再吸收将揭示改变破骨细胞的潜在的新的治疗靶点 治疗破骨细胞介导的骨疾病的活性。