Project Summary/Abstract Bone marrow mesenchymal stromal/stem cells (MSCs) have multiple differentiation potentials and can be induced to differentiate into osteoblasts and adipocytes. MSCs are believed to be the common progenitors for both osteoblasts and adipocytes in bone. As commitment to these two lineages is mutually exclusive, the osteogenic differentiation of MSCs requires coordinated inhibition of the adipogenic differentiation. Aging- related dysfunctions of MSC fate commitment and bone formation have been related to osteoporosis, periodontitis and other metabolic bone diseases. Osteoporosis is the most common metabolic bone disease, and is a leading cause of morbidity and mortality in our aging population. In osteoporosis and skeletal aging, it has been observed that aberrant lineage differentiation of MSCs leads to increasing marrow adipose tissue (MAT) accumulation at the expense of bone formation. Therefore, understanding the molecular mechanisms that control MSC fate determination is critical for developing novel therapeutic strategies for treating osteoporosis and other chronic bone diseases. Peroxisome proliferator-activated receptor-γ coactivators 1α (PGC-1α) is a master regulator of mitochondrial biogenesis and oxidative metabolism in liver, skeletal muscle, brain and the heart, however, its role in bone homeostasis and metabolism remains to be investigated. In this resubmission, we discovered that loss of PGC-1α not only accelerated bone loss, but also enhanced MAT accumulation in osteoporotic and aging mice. Moreover, the specific deletion of Pgc-1α in multipotent mesenchymal cells significantly accelerated MAT accumulation and impaired bone formation in osteoporosis. Loss of PGC-1α reduced cytosolic β-catenin levels and impaired Taz expression, suggesting that PGC-1α regulates MSC fate decision and bone formation. In addition, we found that there was a dramatic decrease in PGC-1α expression in human MSCs during aging. Based on these exciting findings, we hypothesize that PGC-1α plays a critical role in MSC fate decision and bone formation. To test our hypothesis, we propose the following three specific aims: 1) Determine if PGC-1α intrinsically regulates osteogenic differentiation of MSCs and bone formation in osteoporosis and skeletal aging; 2) Determine if PGC-1α intrinsically regulates adipogenic differentiation of MSCs from bone marrow in osteoporosis and skeletal aging; and 3) Explore the molecular mechanisms by which PGC-1α regulates the osteogenic and adipogenic commitment of MSCs. New findings from our studies may identify a novel factor that regulates MSC fate decision and bone formation, and thus presents a promising therapeutic target for osteoporosis and MSC-mediated craniofacial bone regeneration.