RESUMEN
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.