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

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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Adipogenesis and osteogenesis in the cultures of bone marrow cells from ...
Adipogenesis and osteogenesis in the cultures of bone marrow cells from PPARγ+/– and WT littermates. (A) Growth curves of bone marrow cells isolated from PPARγ+/– and WT mice. The adherent bone marrow cells were inoculated at a density of 3 × 105 cells/dish in 10-cm culture dishes. The cells per dish were counted at 1, 2, 3, and 4 days of culture. Data are expressed as means (symbols) ± SEMs (error bars) for eight dishes per group. (B) Adipogenesis determined by oil red O staining in the culture of bone marrow cells in α-MEM/10% FBS with troglitazone. The graph indicates the number of positive cells per square centimeter. (C) Osteogenesis determined by ALP (upper row), Alizarin red (middle row), and von Kossa (lower row) stainings in the culture of bone marrow cells in α-MEM/10% FBS with ascorbic acid and β-glycerophosphate. The graphs below indicate the number of ALP-positive (upper) and Alizarin red–positive (lower) colonies per well. Data are expressed as means (bars) ± SEMs (error bars) for eight wells per group (B and C). *Significant difference from the WT culture, P < 0.01. (D) Expression of key molecules for adipogenesis (PPARγ, C/EBP-β, C/EBP-δ, and C/EBP-α) and osteogenesis (Runx2, osterix, and LRP5), and marker proteins for osteogenesis (COL1A1, ALP, osteocalcin, and osteopontin) determined by quantitative RT-PCR in the bone marrow cells at 14 days of culture under the conditions above. The ordinate axis indicates the relative amount of mRNA as compared with that of WT.