Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ.
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.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Wei
W
Wei
Paul A
PA
Dutchak
Xunde
X
Wang
Xunshan
X
Ding
Xueqian
X
Wang
Angie L
AL
Bookout
Regina
R
Goetz
Moosa
M
Mohammadi
Robert D
RD
Gerard
Paul C
PC
Dechow
David J
DJ
Mangelsdorf
Steven A
SA
Kliewer
Yihong
Y
Wan
D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004351:Drug Resistance / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
D053244:Osteoprotegerin; D047495:PPAR gamma; D053245:RANK Ligand; D045162:Thiazolidinediones; C414620:fibroblast growth factor 21; D000077154:Rosiglitazone; D005346:Fibroblast Growth Factors