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J Biol Chem, Vol. 275, Issue 11, 8126-8132, March 17, 2000

Cloning and Function of Rabbit Peroxisome Proliferator-activated Receptor / in Mature Osteoclasts^*

Hiroshi Mano^§, Chiharu Kimura^¶, Yukio Fujisawa^¶, Takashi Kameda, Mikiko Watanabe-Mano, Hironori Kaneko, Toshio Kaneda, Yoshiyuki Hakeda, and Masayoshi Kumegawa

From the  Department of Oral Anatomy, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-02, Japan, the ^§ Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156, Japan, and the ^¶ Molecular Pharmacology Laboratory, Pharmaceutical Research Division, Pharmaceutical Group, Takeda Chemical Industries, Ltd., 2-17-85 Juso-Honmachi, Yodogawa, Osaka 532, Japan

Osteoclasts modulate bone resorption under physiological and pathological conditions. Previously, we showed that both estrogens and retinoids regulated osteoclastic bone resorption and postulated that such regulation was directly mediated through their cognate receptors expressed in mature osteoclasts. In this study, we searched for expression of other members of the nuclear hormone receptor superfamily in osteoclasts. Using the low stringency homologous hybridization method, we isolated the peroxisome proliferator-activated receptor / (PPAR/) cDNA from mature rabbit osteoclasts. Northern blot analysis showed that PPAR/ mRNA was highly expressed in highly enriched rabbit osteoclasts. Carbaprostacyclin, a prostacyclin analogue known to be a ligand for PPAR/, significantly induced both bone-resorbing activities of isolated mature rabbit osteoclasts and mRNA expression of the cathepsin K, carbonic anhydrase type II, and tartrate-resistant acid phosphatase genes in these cells. Moreover, the carbaprostacyclin-induced bone resorption was completely blocked by an antisense phosphothiorate oligodeoxynucleotide of PPAR/ but not by the sense phosphothiorate oligodeoxynucleotide of the same DNA sequence. Our results suggest that PPAR/ may be involved in direct modulation of osteoclastic bone resorption.

The nucleotide sequence reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number AB033614.

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