PGC-1α Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ

• DOI: 10.1016/j.stem.2018.06.009
• Publication Date: 2018-07-15T05:26:13Z
• Authors: Bo Yu; Lihong Huo; Yunsong Liu; Peng Deng; John Szymanski; Jiong Li; Xianghang Luo; Christine Hong; Jiandie Lin; Cun-Yu Wang
• Keywords: TAZ; Male; 0301 basic medicine; Aging; Biomedical and clinical sciences; PGC-1α; PDZ Domains; Regenerative Medicine; Inbred C57BL; bone; Medical and Health Sciences; Mice; Stem Cell Research - Nonembryonic - Human; fat; 80 and over; 2.1 Biological and endogenous factors; Aged, 80 and over; Mice, Knockout; 0303 health sciences; Stem Cells; Intracellular Signaling Peptides and Proteins; Adaptor Proteins; Skeletal; Biological Sciences; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Biological sciences; Adipose Tissue; Muscle; Stem Cell Research - Nonembryonic - Non-Human; Female; Adult; 570; Knockout; 610; Bone and Bones; Young Adult; 03 medical and health sciences; Animals; Humans; Muscle, Skeletal; Adaptor Proteins, Signal Transducing; Aged; mesenchymal stem cells; aging; Signal Transducing; Stem Cell Research; osteoporosis; Mice, Inbred C57BL; skeletal stem cells; Musculoskeletal; Transcriptional Coactivator with PDZ-Binding Motif Proteins; lineage decision; Trans-Activators; Women's Health; Osteoporosis; Biochemistry and Cell Biology; Transcription Factors; Developmental Biology

Aberrant lineage specification of skeletal stem cells (SSCs) contributes to reduced bone mass and increased marrow adipose tissue (MAT) in osteoporosis and skeletal aging. 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. 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. Loss of PGC-1α promoted adipogenic differentiation of murine SSCs at the expense of osteoblastic differentiation. Deletion of PGC-1α in SSCs impaired bone formation and indirectly promoted bone resorption while enhancing MAT accumulation. Conversely, induction of PGC-1α attenuated osteoporotic bone loss and MAT accumulation. Mechanistically, PGC-1α maintains bone and fat balance by inducing TAZ. Our results suggest that PGC-1α is a potentially important therapeutic target in the treatment of osteoporosis and skeletal aging.