Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ.

TitleFibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ.
Publication TypeJournal Article
Year of Publication2012
AuteursWei, 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
JournalProc Natl Acad Sci U S A
Volume109
Issue8
Pagination3143-8
Date Published2012 Feb 21
ISSN1091-6490
KeywordsAdipogenesis, 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.

DOI10.1073/pnas.1200797109
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22315431
PubMed Central IDPMC3286969
Grant ListR01DK089113 / 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