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 PPARγ, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARγ-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARγ gene. Heterozygous PPARγ-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 PPARγ haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARγ 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 PPARγ-dependent regulation of bone metabolism in vivo, in that PPARγ insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.
Toru Akune, Shinsuke Ohba, Satoru Kamekura, Masayuki Yamaguchi, Ung-il Chung, Naoto Kubota, Yasuo Terauchi, Yoshifumi Harada, Yoshiaki Azuma, Kozo Nakamura, Takashi Kadowaki, Hiroshi Kawaguchi
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