Osteoporosis is defined as a systemic skeletal disease characterized by decreased bone mass and micro-architectural deterioration leading to increased fracture risk. Osteoporosis incidence increases with age in both post-menopausal women and aging men. Among other important contributing factors to bone fragility observed in osteoporosis, that also affect the elderly population, are metabolic disturbances observed in obesity and Type 2 Diabetes (T2D). These metabolic complications are associated with impaired bone homeostasis and a higher fracture risk. Expansion of the Bone Marrow Adipose Tissue (BMAT), at the expense of decreased bone formation, is thought to be one of the key pathogenic mechanisms underlying osteoporosis and bone fragility in obesity and T2D. Our review provides a summary of mechanisms behind increased Bone Marrow Adiposity (BMA) during aging and highlights the pre-clinical and clinical studies connecting obesity and T2D, to BMA and bone fragility in aging osteoporotic women and men.

Secreted factors are a key component of stem cell niche and their dysregulation compromises stem cell function. Legumain is a secreted cysteine protease involved in diverse biological processes. Here, we demonstrate that legumain regulates lineage commitment of human bone marrow stromal cells and that its expression level and cellular localization are altered in postmenopausal osteoporotic patients. As shown by genetic and pharmacological manipulation, legumain inhibited osteoblast (OB) differentiation and in vivo bone formation through degradation of the bone matrix protein fibronectin. In addition, genetic ablation or pharmacological inhibition of legumain activity led to precocious OB differentiation and increased vertebral mineralization in zebrafish. Finally, we show that localized increased expression of legumain in bone marrow adipocytes was inversely correlated with adjacent trabecular bone mass in a cohort of patients with postmenopausal osteoporosis. Our data suggest that altered proteolytic activity of legumain in the bone microenvironment contributes to decreased bone mass in postmenopausal osteoporosis.

Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. Significance: This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.

Mechanisms controlling human multipotent mesenchymal (stromal) stem cell (hMSC) differentiation into osteoblasts or adipocytes are poorly understood. We have previously demonstrated that Wnt signaling in hMSC enhanced osteoblast differentiation and inhibited adipogenesis by comparing two hMSC cell lines overexpressing mutated forms of the Wnt co-receptor LRP5: T253I (hMSC-LRP5^T253) and T244M (hMSC-LRP5^T244) conducting high and low level of Wnt signaling, respectively. To explore the underlying molecular mechanisms, we compared gene expression profiles of hMSC-LRP5^T253 and hMSC-LRP5^T244 treated with Wnt3a using whole genome expression microarrays and found that TNFRSF19 is differentially up-regulated between the two cells lines. Bioinformatic analysis and dual luciferase assay of its promoter revealed that TNFRSF19 transcript 2 (TNFRSF19.2) is a target of canonical Wnt signaling. Knocking down TNFRSF19 in hMSC-LRP5^T253 cells decreased Wnt3a-induced osteoblast differentiation marker alkaline phosphate activity and its overexpression in hMSC-LRP5^T244 cells increased alkaline phosphate activity. In addition, TNFRSF19 was negatively regulated by adipogenic transcription factor CCAAT/enhancer-binding proteins (C/EBP). Knocking down TNFRSF19 in hMSC-LRP5^T253 cells or its overexpression in hMSC-LRP5^T244 cells significantly increased or decreased adipogenesis, respectively. In conclusion, we revealed a novel function of TNFRSF19 as a factor mediating differentiation signals that determine the hMSC differentiating fate into osteoblasts or adipocytes.

Aging is associated with decreased bone mass and accumulation of bone marrow adipocytes. Both bone forming osteoblastic cells and bone marrow adipocytes are derived from a stem cell population within the bone marrow stroma called bone marrow stromal (skeletal or mesenchymal) stem cells (BMSC). In the present review, we provide an overview, based on the current literature, regarding the physiological aging processes that cause changes in BMSC lineage allocation, enhancement of adipocyte and defective osteoblast differentiation, leading to gradual exhaustion of stem cell regenerative potential and defects in bone tissue homeostasis and metabolism. We discuss strategies to preserve the "youthful" state of BMSC, to reduce bone marrow age-associated adiposity, and to counteract the overall negative effects of aging on bone tissues with the aim of decreasing bone fragility and risk of fractures.