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Cell Stem Cell. 2018 Aug 2;23(2):193-209.e5. doi: 10.1016/j.stem.2018.06.009. Epub 2018 Jul 12.

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

Author information

1
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: boyu@dentistry.ucla.edu.
2
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Department of Prosthodontics, School of Stomatology, Peking University, Beijing 100081, China.
4
Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, People's Republic of China.
5
Division of Growth and Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Life Sciences Institute, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
7
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, Broad Stem Cell Research Center and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: cwang@dentistry.ucla.edu.

Abstract

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.

KEYWORDS:

PGC-1α; TAZ; aging; bone; fat; lineage decision; mesenchymal stem cells; osteoporosis; skeletal stem cells

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