Increased marrow adipose tissue (MAT) accumulation takes place at the expense of bone formation and in turn impairs osteogenic regeneration and hematopoiesis ( Ambrosi et al., 2017). In addition to the established paradigm where osteoporosis is caused by an imbalance between osteoclasts and osteoblasts, emerging evidence suggests another pathogenic process involving aberrant lineage allocation of SSCs ( Devlin and Rosen, 2015 Fan et al., 2017 Ye et al., 2012). Osteoporosis is the most common metabolic bone disease, posing a substantial public health burden in our aging population. Consistent with this reciprocal relationship, multiple cross-sectional human studies have also confirmed correlations between high marrow fat content, low bone density, and increased fracture risk, particularly in the context of osteoporosis and skeletal aging ( Fazeli et al., 2013 Schwartz, 2015 Zaidi et al., 2012). With the exception of certain animal strains or models ( Ackert-Bicknell et al., 2009 Justesen et al., 2004), the commitment toward these lineages is classically considered to be inversely related, as the osteogenic differentiation of SSCs requires a coordinated inhibition of adipogenic differentiation ( Kawai and Rosen, 2010 McCauley, 2010). Recent lineage-tracing efforts further identify a shared reservoir of multipotent progenitors residing in the perivascular niche that can become unilaterally committed to either an osteogenic or adipogenic lineage ( Ambrosi et al., 2017 Zhou et al., 2014). Skeletal stem cells (SSCs) are a subset of bone marrow stromal cells with the ability of self-renewal and multiple lineage potentials contributing to the osteoblast and adipocyte progenies in the adult bone marrow ( Bianco et al., 2013 Bianco and Robey, 2015 Zhou et al., 2014). Our results suggest that PGC-1α is a potentially important therapeutic target in the treatment of osteoporosis and skeletal aging. Mechanistically, PGC-1α maintains bone and fat balance by inducing TAZ. Conversely, induction of PGC-1α attenuated osteoporotic bone loss and MAT accumulation. Deletion of PGC-1α in SSCs impaired bone formation and indirectly promoted bone resorption while enhancing MAT accumulation. Loss of PGC-1α promoted adipogenic differentiation of murine SSCs at the expense of osteoblastic differentiation. Here, we identify peroxisome-proliferator-activated receptor 𝛄 coactivator 1-α (PGC-1α) as a critical switch of cell fate decisions whose expression decreases with aging in human and mouse SSCs. Although master regulators of osteoblastic and adipogenic lineages have been identified, little is known about factors that are associated with MAT accumulation and osteoporotic bone loss. Aberrant lineage specification of skeletal stem cells (SSCs) contributes to reduced bone mass and increased marrow adipose tissue (MAT) in osteoporosis and skeletal aging.
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