Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: Increased serum concentrations in postmenopausal women with osteoporosis

Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) is a solu ble member of the tumor necrosis factor receptor family of proteins and pla ys an important role in the negative regulation of osteoclastic hone resorp tion, Whether OPG/OCIF circulates in human blood and how its level changes under pathological conditions is not known. To address these issues, a pane l of monoclonal antibodies was generated against recombinant OPG/OCIF and s creened for reactivity with solid-phase monomeric and homodimeric forms of the recombinant protein. Antibodies that showed high affinity for both form s of OPG/OCIF and those that selectively recognized the homodimer were iden tified, enabling development of two types of sensitive enzyme-linked immuno sorbent assay (ELISA): one that detects both forms of OPG/OCIF equally and one specific for the homodimer. Characterization of circulating OPG/OCIF wi th these ELISAs revealed that the protein exists in human serum mainly in t he monomeric form. The serum concentration of OPG/OCIF increased with age i n both healthy Japanese men and nomen, and was significantly higher in post menopausal women with osteoporosis than in age-matched controls, Within the osteoporotic group, serum OPG/OCIF concentrations were higher in patients with low bone mass. Serum OPG/OCIF concentrations were also significantly i ncreased in those postmenopausal women with a high rate of bone turnover, a s determined by increased serum bone-specific alkaline phosphatase and urin ary excretion of pyridinoline and deoxypyridinoline. The results suggested that circulating OPG/OCIF levels are regulated by an age-related factor(s) and that the increased serum concentration may reflect a compensative respo nse to enhanced osteoclastic bone resorption and the resultant bone loss ra ther than a cause of osteoporosis.