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Human Osteoclast-Like Cells Are Formed from Peripheral Blood Mononuclear Cells in a Coculture with SaOS-2 Cells Transfected with the Parathyroid Hormone (PTH)/PTH-Related Protein Receptor Gene

Department of Biochemistry, School of Dentistry, Showa University (K.M., I.N., N.U., T.T., N.T., T.S.), 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555; Asahi Chemical Industry Company, Ltd., Laboratory for Bone Metabolism (K.K., Y.T., M.H.), 632–1 Mifuku, Ohito-cho, Tagata-gun, Shizuoka 410-2321; Institute of Medical Science University of Tokyo (R.N.), 4–6-1 Shiroganedai, Minato-ku, Tokyo 108-0071; and Department of Orthopaedic Surgery, School of Medicine, Keio University (K.M., Y.T., Y.Y.), 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan

Address all correspondence and requests for reprints to: Yasuyuki Takahashi, Asahi Chemical Industry Company, Ltd., Laboratory for Bone Metabolism, 632–1 Mifuku, Ohito-cho, Tagata-gun, Shizuoka 410-2321, Japan. E-mail: a7911076{at}ut.asahi-kasei.co.jp

Subclones of the human osteosarcoma cell line SaOS-2 were established by transfecting with an expression vector containing the human PTH/PTH-related protein (PTHrP) receptor, and their abilities to support osteoclast-like multinucleated cell (OCL) formation were examined in coculture with mouse or human hemopoietic cells. Of four subclones examined, SaOS-2/4 and SaOS-4/3 bound high levels of [¹²⁵I]-PTH and produced a significant amount of cAMP in response to PTH. OCLs were formed in response to PTH in the cocultures of mouse bone marrow cells with either SaOS-2/4 cells or SaOS-4/3 cells. Human OCLs were also formed in response to PTH in the coculture of SaOS-4/3 cells and human peripheral blood mononuclear cells. Adding dexamethasone together with PTH greatly enhanced PTH-induced human OCL formation. Like mouse OCLs, human OCLs formed in response to PTH were tartrate-resistant acid phosphatase positive, expressed abundant calcitonin receptors and vitronectin receptors, and formed resorption pits on dentine slices. Other osteotropic factors such as 1,25-dihydroxyvitamin D₃, prostaglandin E₂, and interleukin 6 plus soluble interleukin 6 receptors failed to induce mouse and human OCLs in cocultures with SaOS-4/3 cells. Both mouse and human OCL formation supported by SaOS-4/3 cells were inhibited by either adding an antibody against macrophage-colony stimulating factor or adding granulocyte/macrophage-colony stimulating factor. Thus, it is likely that human and mouse OCL formation supported by SaOS-4/3 cells are similarly regulated. These results indicate that the target cells of PTH for inducing osteoclast formation are osteoblast/stromal cells but not osteoclast progenitor cells in the coculture. This coculture model will be useful for investigating the abnormalities of osteoclast differentiation and function in human metabolic bone diseases.

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