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Osteoprotegerin Produced by Osteoblasts Is an Important Regulator in Osteoclast Development and Function*

2000; Oxford University Press; Volume: 141; Issue: 9 Linguagem: Inglês

10.1210/endo.141.9.7634

1945-7170

Nobuyuki Udagawa, Naoyuki Takahashi, Hisataka Yasuda, Atsuko Mizuno, Kanami Itoh, Y Ueno, Toshimasa Shinki, Matthew T. Gillespie, T. John Martin, Kanji Higashio, Tatsuo Suda,

Pharmacological Effects of Medicinal Plants

Osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-κB ligand (RANKL)/osteoclast differentiation factor, inhibits both differentiation and function of osteoclasts. We previously reported that OPG-deficient mice exhibited severe osteoporosis caused by enhanced osteoclastic bone resorption. In the present study, potential roles of OPG in osteoclast differentiation were examined using a mouse coculture system of calvarial osteoblasts and bone marrow cells prepared from OPG-deficient mice. In the absence of bone-resorbing factors, no osteoclasts were formed in cocultures of wild-type (+/+) or heterozygous (+/−) mouse-derived osteoblasts with bone marrow cells prepared from homozygous (−/−) mice. In contrast, homozygous (−/−) mouse-derived osteoblasts strongly supported osteoclast formation in the cocultures with homozygous (−/−) bone marrow cells, even in the absence of bone-resorbing factors. Addition of OPG to the cocultures with osteoblasts and bone marrow cells derived from homozygous (−/−) mice completely inhibited spontaneously occurring osteoclast formation. Adding 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] to these cocultures significantly enhanced osteoclast differentiation. In addition, bone-resorbing activity in organ cultures of fetal long bones derived from homozygous (−/−) mice was markedly increased, irrespective of the presence and absence of bone-resorbing factors, in comparison with that from wild-type (+/+) mice. Osteoblasts prepared from homozygous (−/−), heterozygous (+/−), and wild-type (+/+) mice constitutively expressed similar levels of RANKL messenger RNA, which were equally increased by the treatment with 1α,25(OH)2D3. When homozygous (−/−) mouse-derived osteoblasts and hemopoietic cells were cocultured, but direct contact between them was prevented, no osteoclasts were formed, even in the presence of 1α,25(OH)2D3 and macrophage colony-stimulating factor. These findings suggest that OPG produced by osteoblasts/stromal cells is a physiologically important regulator in osteoclast differentiation and function and that RANKL expressed by osteoblasts functions as a membrane-associated form.