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Prostaglandin E₂ Strongly Inhibits Human Osteoclast Formation

Graduate School of Oral Medicine (I.T.), Institute for Oral Science (Y.K., N.T.), Department of Orthodontics (I.T., S.U., N.O., S.K.), and Department of Biochemistry (N.U.), Matsumoto Dental University, Nagano 399-0781, Japan; Department of Periodontology (Y.Y.), School of Dentistry, Aichi Gakuin University, Nagoya 464-8651, Japan; Department of Orthopedic Surgery, Osaka University Graduate School of Medicine (H.T.), Osaka 565-0871, Japan; and National Hospital Organization Sagamihara National Hospital (T.O.), Kanagawa 228-8522, Japan

Address all correspondence and requests for reprints to: Dr. Naoyuki Takahashi, Institute for Oral Science, Matsumoto Dental University, 1780 Hiro-oka Gobara, Shiojiri, Nagano 399-0781, Japan. E-mail: takahashinao{at}po.mdu.ac.jp.

Prostaglandin E₂ (PGE₂) enhances osteoclast formation in mouse macrophage cultures treated with receptor activator of nuclear factor-B ligand (RANKL). The effects of PGE₂ on human osteoclast formation were examined in cultures of CD14⁺ cells prepared from human peripheral blood mononuclear cells. CD14⁺ cells differentiated into osteoclasts in the presence of RANKL and macrophage colony-stimulating factor. CD14⁺ cells expressed EP2 and EP4, but not EP1 or EP3, whereas CD14⁺ cell-derived osteoclasts expressed none of the PGE₂ receptors. PGE₂ and PGE₁ alcohol (an EP2/4 agonist) stimulated cAMP production in CD14⁺ cells. In contrast to mouse macrophage cultures, PGE₂ and PGE₁ alcohol inhibited RANKL-induced human osteoclast formation in CD14⁺ cell cultures. H-89 blocked the inhibitory effect of PGE₂ on human osteoclast formation. These results suggest that the inhibitory effect of PGE₂ on human osteoclast formation is mediated by EP2/EP4 signals. SaOS4/3 cells have been shown to support human osteoclast formation in cocultures with human peripheral blood mononuclear cells in response to PTH. PGE₂ inhibited PTH-induced osteoclast formation in cocultures of SaOS4/3 cells and CD14⁺ cells. Conversely, NS398 (a cyclooxygenase 2 inhibitor) enhanced osteoclast formation induced by PTH in the cocultures. The conditioned medium of CD14⁺ cells pretreated with PGE₂ inhibited RANKL-induced osteoclast formation not only in human CD14⁺ cell cultures, but also in mouse macrophage cultures. These results suggest that PGE₂ inhibits human osteoclast formation through the production of an inhibitory factor(s) for osteoclastogenesis of osteoclast precursors.

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