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

摘要 与年龄相关的骨丢失使个人面临虚弱的骨质疏松性骨折的风险。当前骨质疏松症 治疗主要针对骨吸收破骨细胞，以防止进一步的骨丢失；然而，由于 破骨细胞和成骨细胞的结合，这些治疗受到伴随的骨质减少的限制。 队形。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。 队形。破骨细胞是来源于髓系的多核细胞。虽然最出名的是 骨吸收，破骨细胞表现出一系列的功能，包括刺激成骨细胞的骨形成 (耦合活动)。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 本文证实，并不是所有的破骨细胞都在主动吸收或偶联，其他人已经记录了 破骨细胞吸收活动本身的异质性。随着年龄的增长，破骨细胞的功能分布发生了变化， 随着主动吸收破骨细胞百分比的增加和阳性破骨细胞的减少 耦合因子表达式。衰老还会导致侵袭性破骨细胞亚群的增加，这是 在吸收骨骼的同时移动，导致海沟的形成。我们的数据支持这些侵略性的、形成壕沟的 破骨细胞表现出更大的吸收陷窝酸化和更高的蛋白酶活性 将骨祖细胞招募到吸收部位的能力受损。因此，我们假设 随着年龄的增长，侵略性的、形成海沟的破骨细胞与破骨细胞偶联活性降低有关，导致 全身骨质流失。为了验证这一假设，我们建议1)确定破骨细胞的可诱导激活 偶联活动可防止与年龄相关的骨丢失；2)评估不同的破骨细胞是否发生骨吸收 行为影响偶联；以及3)测试基质衍生转化生长因子-β作为反馈机制的作用 调节破骨细胞的活动。总之，这些研究将揭示破骨细胞行为的分布和 这些在衰老过程中是如何失调的。此外，了解变化的机制 吸收导致偶联活性改变将揭示转移破骨细胞的潜在治疗靶点 治疗破骨细胞介导性骨病的活动。

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.