FGF21 Is Not a Major Mediator for Bone Homeostasis or Metabolic Actions of PPAR and PPAR Agonists

Results of prior studies suggest that fibroblast growth factor 21 (FGF21) may be involved in bone turnover and in the actions of peroxisome proliferator-activated receptor (PPAR) and in mice. We have conducted independent studies to examine the effects of FGF21 on bone homeostasis and the role of FGF21 in PPAR and actions. High-fat-diet-induced obesity (DIO) mice were administered vehicle or recombinant human FGF21 (rhFGF21) intraperitoneally at 0 (vehicle), 0.1, 1, and 3mg/kg daily for 2 weeks. Additional groups of DIO mice received water or 10mg/kg rosiglitazone daily. Mice treated with rhFGF21 or rosiglitazone showed expected metabolic improvements in glucose, insulin, and lipid levels. However, bone loss was not detected in rhFGF21-treated mice by dual-energy X-ray absorptiometry (DXA), micro-CT, and histomorphometric analyses. Mineral apposition rate, a key bone formation parameter, was unchanged by rhFGF21, while significantly decreased by rosiglitazone in DIO mice. Bone resorption markers, OPG/RANKL mRNA expression, and histological bone resorption indices were unchanged by rhFGF21 or rosiglitazone. Bone marrow fat was unchanged by rhFGF21, while increased by rosiglitazone. Furthermore, FGF21 knockout mice did not show high bone mass phenotype. Treatment with PPAR or PPAR agonists caused similar metabolic effects in FGF21 knockout and wild-type mice. These results contrast with previous findings and suggest that FGF21 is not critical for bone homeostasis or actions of PPAR and PPAR. (c) 2016 American Society for Bone and Mineral Research.