Bone formation requires the replenishment of the osteoblast from a progenitor or stem cell population, which must be recruited, expanded, and differentiated to ensure continued anabolism. How this occurs and whether it is altered in the osteoporotic environment is poorly understood. Furthermore, given that emerging treatments for osteoporosis are targeting this progenitor population, it is critical to determine the regenerative capacity of this cell type in the setting of osteoporosis. Human bone marrow stromal cells (hMSCs) from a cohort of aged osteoporotic patients were compared to MSCs isolated from healthy donors in terms of the ability to undergo recruitment and proliferation, and also respond to both the biophysical and biochemical cues that drive osteogenic matrix deposition. hMSCs isolated from healthy donors demonstrate good recruitment, mechanosensitivity, proliferation, and differentiation capacity. Contrastingly, hMSCs isolated from aged osteoporotic patients had significantly diminished regenerative potential. Interestingly, we demonstrated that osteoporotic hMSCs no longer responded to chemokine-directing recruitment and became desensitised to mechanical stimulation. The osteoporotic MSCs had a reduced proliferative potential and, importantly, they demonstrated an attenuated differentiation capability with reduced mineral and lipid formation. Moreover, during osteogenesis, despite minimal differences in the quantity of deposited collagen, the distribution of collagen was dramatically altered in osteoporosis, suggesting a potential defect in matrix quality. Taken together, this study has demonstrated that hMSCs isolated from aged osteoporotic patients demonstrate defective cell behaviour on multiple fronts, resulting in a significantly reduced regenerative potential, which must be considered during the development of new anabolic therapies that target this cell population.

中文翻译：

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老年骨质疏松性骨髓基质细胞表现出有缺陷的募集、机械敏感性和基质沉积

骨形成需要从祖细胞或干细胞群中补充成骨细胞，这些细胞必须被募集、扩增和分化以确保持续合成代谢。这是如何发生的，以及它是否在骨质疏松环境中发生改变，我们知之甚少。此外，鉴于骨质疏松症的新兴疗法针对的是这一祖细胞群，因此在骨质疏松症的背景下确定这种细胞类型的再生能力至关重要。将来自老年骨质疏松患者队列的人骨髓基质细胞 (hMSC) 与从健康供体分离的 MSC 在募集和增殖能力方面进行比较，并对驱动成骨基质沉积的生物物理和生化线索作出反应。从健康供体中分离出的 hMSC 表现出良好的募集，机械敏感性、增殖和分化能力。相比之下，从老年骨质疏松患者中分离的 hMSCs 的再生潜力显着降低。有趣的是，我们证明骨质疏松的 hMSCs 不再对趋化因子导向的募集做出反应，并且对机械刺激变得不敏感。骨质疏松性 MSCs 的增殖潜力降低，重要的是，它们表现出减弱的分化能力，减少矿物质和脂质的形成。此外，在成骨过程中，尽管沉积胶原蛋白的数量差异很小，但骨质疏松症中胶原蛋白的分布发生了显着变化，表明基质质量存在潜在缺陷。综合起来，