Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 8, Pages 3143-3148Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1200797109
Keywords
bone metabolism; osteoblast; thiazolidinediones; adipocyte; nuclear receptor
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Funding
- University of Texas
- Cancer Prevention and Research Institute of Texas [RP100841]
- March of Dimes Grant [5-FY10-1]
- Welch Foundation [I-1751, I-1275, I-1558]
- National Institutes of Health (NIH) [R01DK089113, RL1GM084436, R56DK089600, U19DK062434, GM007062, DE13686]
- Howard Hughes Medical Institute
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The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor gamma (PPAR-gamma). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-gamma agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.
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