Title | Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Auteurs | Wei, W, Dutchak, P, Wang, X, Ding, X, Wang, X, Bookout, AL, Goetz, R, Mohammadi, M, Gerard, RD, Dechow, PC, Mangelsdorf, DJ, Kliewer, SA, Wan, Y |
Journal | Proc Natl Acad Sci U S A |
Volume | 109 |
Issue | 8 |
Pagination | 3143-8 |
Date Published | 2012 Feb 21 |
ISSN | 1091-6490 |
Keywords | Adipogenesis, Animals, Bone and Bones, Bone Marrow, Bone Resorption, Drug Resistance, Fibroblast Growth Factors, Humans, Mice, Mice, Knockout, Organ Size, Osteoblasts, Osteogenesis, Osteoprotegerin, PPAR gamma, RANK Ligand, Rosiglitazone, Thiazolidinediones |
Abstract | 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 γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ 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. |
DOI | 10.1073/pnas.1200797109 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 22315431 |
PubMed Central ID | PMC3286969 |
Grant List | R01DK089113 / DK / NIDDK NIH HHS / United States R56DK089600 / DK / NIDDK NIH HHS / United States R56 DK089600 / DK / NIDDK NIH HHS / United States U19 DK062434 / DK / NIDDK NIH HHS / United States T32 GM007062 / GM / NIGMS NIH HHS / United States U19DK062434 / DK / NIDDK NIH HHS / United States RL1GM084436 / GM / NIGMS NIH HHS / United States / / Howard Hughes Medical Institute / United States DE13686 / DE / NIDCR NIH HHS / United States R01 DE013686 / DE / NIDCR NIH HHS / United States RL1 GM084436 / GM / NIGMS NIH HHS / United States GM007062 / GM / NIGMS NIH HHS / United States R01 DK089113 / DK / NIDDK NIH HHS / United States |