Journal Article

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

Bookout, Angie L, Dechow, Paul C, Wei, Wei, Wan, Yihong, Wang, Xunde, Ding, Xunshan, Mohammadi, Moosa, Dutchak, Paul A, Mangelsdorf, David J, Wang, Xueqian, Gerard, Robert D, Goetz, Regina, Kliewer, Steven A

2012

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adipocytes / adipogenesis / Adipogenesis - drug effects / adverse effects / agonists / Animals / Biological Sciences / Bone and Bones - drug effects / Bone and Bones - metabolism / Bone and Bones - pathology / bone density / Bone formation / Bone loss / Bone marrow / Bone Marrow - drug effects / Bone Marrow - pathology / Bone mass / Bone resorption / Bone Resorption - metabolism / Bone Resorption - pathology / Bone turnover / Bones / Diabetes mellitus / Drug Resistance - drug effects / Drugs / Energy metabolism / Fibroblast growth factor / Fibroblast growth factors / Fibroblast Growth Factors - administration & dosage / Fibroblast Growth Factors - metabolism / Fibroblast Growth Factors - pharmacology / Gene expression regulation / glucose / Glucose metabolism / Homeostasis / Hormones / Humans / Lipid metabolism / Mesenchyme / Mice / Mice, Knockout / noninsulin-dependent diabetes mellitus / Organ Size - drug effects / Osteoblastogenesis / Osteoblasts / Osteoblasts - drug effects / Osteoblasts - metabolism / Osteoblasts - pathology / Osteoclasts / Osteogenesis - drug effects / Osteoprotegerin - metabolism / Peroxisome proliferator-activated receptors / phenotype / PPAR gamma - metabolism / RANK Ligand - metabolism / rosiglitazone / Side effects / Stem cells / Thiazolidinediones - pharmacology / Type 2 diabetes mellitus