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Osteoblasts Provide a Suitable Microenvironment for the Action of Receptor Activator of Nuclear Factor-B Ligand

Department of Periodontology (Y.Y., T.N.), School of Dentistry, Aichi-Gakuin University, 464-8650 Aichi, Japan; Department of Biochemistry (Y.Y., N.U., M.N.), Second Department of Anatomy (S.M., A.H.), and Institute for Oral Science (Y.N., H.O., N.T.), Matsumoto Dental University, Nagano 399-0781, Japan; Department of Orthopedic Surgery (H.H.), Shinshu University, School of Medicine, Nagano 390-8621, Japan; Department of Orthopaedic Surgery (K.T.), Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), A-1030 Vienna, Austria

Address all correspondence and requests for reprints to: Nobuyuki Udagawa, Department of Biochemistry, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan. E-mail: udagawa{at}po.mdu.ac.jp.

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-B ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption. Serum concentrations of RANKL are extremely high in OPG-deficient (OPG^–/–) mice, suggesting that circulating RANKL is involved in osteoclastogenesis. RANKL^–/– mice exhibit osteopetrosis, with the absence of osteoclasts. We examined the requirements for osteoclastogenesis using OPG^–/– mice, RANKL^–/– mice, and a system involving bone morphogenetic protein 2 (BMP-2)-induced ectopic bone formation. When collagen disks containing BMP-2 (BMP-2-disks) or vehicle were implanted into OPG^–/– mice, osteoclast-like cells (OCLs) and alkaline phosphatase-positive OCLs appeared in BMP-2-disks but not the control disks. F4/80-positive osteoclast precursors were similarly distributed in both BMP-2- and control disks. Cells expressing RANKL were detected in the BMP-2-disks, and the addition of OPG to the disk inhibited OCL formation. Muscle cells in culture differentiated into alkaline phosphatase-positive cells in the presence of BMP-2 and accordingly expressed RANKL mRNA in response to PTH. This suggests that RANKL expressed by osteoblasts is a requirement for osteoclastogenesis. We then examined how osteoblasts are involved in osteoclastogenesis other than RANKL expression, using RANKL^–/– mice. BMP-2- and control disks were implanted into RANKL^–/– mice, which were injected with RANKL for 7 d. Many OCLs were observed in the BMP-2-disks and bone tissues but not the control disks. These results suggest that osteoblasts also play important roles in osteoclastogenesis through offering the critical microenvironment for the action of RANKL.