PPAR γ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors

Abstract

Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPAR , a key regulator of adipocyte differentiation, in bone metabolism.Homozygous PPAR -deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPAR gene.Heterozygous PPAR -deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin.The osteogenic effect of PPAR haploinsufficiency became prominent with aging but was not changed upon ovariectomy.The PPAR haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells.This study demonstrates a PPAR dependent regulation of bone metabolism in vivo, in that PPAR insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.Nonstandard abbreviations used: alkaline phosphatase (ALP); bone morphogenetic protein-2 (BMP-2); bone volume (BV); CCAAT enhancer-binding proteins (C/EBPs); computed tomography (CT); LDL receptor-related protein 5 (LRP5); leukemia inhibitory factor (LIF); M-CSF-dependent bone marrow macrophage (M-BMM); receptor activator of nuclear factor B ligand (RANKL); ovariectomy (OVX); PPAR responsive element (PPRE); tartrate-resistant acid phosphatase (TRAP); tissue volume (TV); type I collagen 1 chain (COL1A1).