Peroxisome proliferator activated receptor-γ in osteoblasts controls bone formation and fat mass by regulating sclerostin expression
Soohyun P. Kim,
Avery H. Seward,
Jean Garcia-Diaz,
Nathalie Alekos,
Nicole R. Gould,
Susan Aja,
Joseph P. Stains,
Michael J. Wolfgang,
Ryan C. Riddle
Affiliations
Soohyun P. Kim
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Avery H. Seward
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Jean Garcia-Diaz
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Nathalie Alekos
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Nicole R. Gould
Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Susan Aja
Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Joseph P. Stains
Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Michael J. Wolfgang
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Ryan C. Riddle
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Research and Development Service, Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA; Corresponding author
Summary: The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a key contributor to metabolic function via its adipogenic and insulin-sensitizing functions, but it has negative effects on skeletal homeostasis. Here, we questioned whether the skeletal and metabolic actions of PPARγ are linked. Ablating Pparg expression in osteoblasts and osteocytes produced a high bone mass phenotype, secondary to increased osteoblast activity, and a reduction in subcutaneous fat mass because of reduced fatty acid synthesis and increased fat oxidation. The skeletal and metabolic phenotypes in Pparg mutants proceed from the regulation of sclerostin production by PPARγ. Mutants exhibited reductions in skeletal Sost expression and serum sclerostin levels while increasing production normalized both phenotypes. Importantly, disrupting the production of sclerostin synergized with the insulin-sensitizing actions of a PPARγ agonist while preventing bone loss. These data suggest that modulating sclerostin action may prevent bone loss associated with anti-diabetic therapies and augment their metabolic actions.
