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PPAR γ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors
Toru Akune, … , Takashi Kadowaki, Hiroshi Kawaguchi
Toru Akune, … , Takashi Kadowaki, Hiroshi Kawaguchi
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):846-855. https://doi.org/10.1172/JCI19900.
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Article Bone biology

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

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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 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.

Authors

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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Figure 1

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Adipogenesis and osteogenesis in the mouse ES cell cultures of homozygou...
Adipogenesis and osteogenesis in the mouse ES cell cultures of homozygous PPARγ-deficient (PPARγ–/–) and WT genotypes. As a rescue experiment, PPARγ was reintroduced into PPARγ–/– ES cells using a retrovirus vector carrying the PPARγ gene (Rx-PPARγ) or the same retrovirus vector without the PPARγ gene (Rx-vector) as a control. (A) The upper row shows the adipogenesis determined by the oil red O staining of the ES cell culture in DMEM/10% FBS with troglitazone. The number of oil red O–positive cells stained in red was counted and shown in the left graph as the cells per square centimeter. The images in the lower row indicate the osteogenesis determined by the von Kossa staining of the ES cell culture in DMEM/10% FBS without any osteogenic supplements. The number of von Kossa–positive calcified nodules stained in black was counted and shown in the right graph as the number per square centimeter. Scale bar: 20 μm. (B) Relative mRNA levels of the marker genes for osteoblasts — COL1A1, osteocalcin and Runx2 — determined by real-time quantitative RT-PCR 10 days after the embryoid bodies were transferred to a gelatinized six-multiwell plate in DMEM/10% FBS without any osteogenic supplements. The ordinate axis indicates the relative amount of mRNA as compared with that of WT. Data are expressed as means (bars) ± SEMs (error bars) for eight wells per group. *Significant difference from the WT culture, P < 0.01. #Significant restoration by Rx-PPARγ as compared with the control PPARγ–/– and PPARγ–/– plus Rx-vector cultures; P < 0.01. Cont, control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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