(T1020) METABOLIC DYSREGULATION IN BONE MARROW MESENCHYMAL STEM CELLS: IMPLICATIONS FOR OSTEOPOROTIC FRAGILITY IN WOMEN

Abstract: Bone marrow mesenchymal stem cells (BM-MSCs) are critical for bone homeostasis, yet aging and osteoporosis (OP) impair their function, contributing to bone fragility and fracture risk. Despite their importance, the metabolic mechanisms underlying BM-MSC dysfunction in aging and OP remain poorly understood. This study investigates the cellular metabolism of BM-MSCs from young healthy (n=6), elderly healthy (n=3), and elderly OP (n=5) women, and correlating seahorse-based quantification of oxidative and glycolytic activities with bone mineral density (BMD) from DEXA scans. Our preliminary results show significant reductions in BMD across different skeletal sites. As expected, BMD declined at the lumbar spine, femoral neck, and total hip in elderly subjects, with BMD reaching T-score below -2.5 in the osteoporotic group. Metabolic profiling revealed altered glycolytic activity in BM-MSCs, with extracellular acidification rate (ECAR) and glycolytic ATP production decreased by 61% in elderly OP women compared to young healthy controls (P < 0.05). Elderly healthy women showed trends toward reduced ECAR (35%) and glycolytic ATP (22%), though not significant. Alike the decline in BMD observed from young over elderly to osteoporotic subjects, a stepwise decrease was found in the glycolytic activity of isolated BM-MSCs in vitro. This suggests that the cells exhibit an intrinsic metabolic defect that aligns with the general decline of bone formation observed in elderly and osteoporotic subjects. To explore these findings further, we will implant BM-MSCs from these donors subcutaneously into immunodeficient female mice to assess their capacity to form bone. Additionally, we will use single-cell RNA sequencing to investigate the transcriptional pathways driving metabolic dysregulation in BM-MSCs and their impaired osteogenic potential. These results highlight the critical role of metabolic alterations in BM-MSCs in the pathophysiology of osteoporosis, suggesting that targeting metabolic pathways could offer novel strategies to mitigate bone loss and improve bone regeneration in aging populations.

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