The physiological role of osteoclast differentiation factor.

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Osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-κB ligand (RANKL)/osteoclast differentiation factor (ODF), 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 co-culture 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 co-cultures 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 co-cultures with homozygous (-/-) bone marrow cells even in the absence of bone-resorbing factors. Addition of OPG to the co-cultures with osteoblasts … More 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 co-cultures 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 mRNA, which were equally increased by the treatment with 1α, 25(OH)2D3. When homozygous (-/-) mouse-derived osteoblasts and hemopoietic cells were co-cultured, but direct contact between them was prevented, no osteoclasts were formed even in the presence of 1α, 25(OH)2D3 and M-CSF.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. Less