Immunological Characterization of Circulating Osteoprotegerin/Osteoclastogenesis Inhibitory Factor: Increased Serum Concentrations in Postmenopausal Women with Osteoporosis

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  • Kazuki Yano
    Research Institute of Life Science, Snow Brand Milk Products Co., Ltd, Shimotsuga-gun, Tochigi, Japan
  • Eisuke Tsuda
    Research Institute of Life Science, Snow Brand Milk Products Co., Ltd, Shimotsuga-gun, Tochigi, Japan
  • Naohiro Washida
    Research Institute of Life Science, Snow Brand Milk Products Co., Ltd, Shimotsuga-gun, Tochigi, Japan
  • Fumie Kobayashi
    Research Institute of Life Science, Snow Brand Milk Products Co., Ltd, Shimotsuga-gun, Tochigi, Japan
  • Masaaki Goto
    Research Institute of Life Science, Snow Brand Milk Products Co., Ltd, Shimotsuga-gun, Tochigi, Japan
  • Atsushi Harada
    Division of Orthopedic Surgery, National Chubu Hospital, Obu, Aichi, Japan
  • Kyoji Ikeda
    Department of Geriatric Research, National Institute for Longevity Sciences, Obu, Aichi, Japan
  • Kanji Higashio
    Research Institute of Life Science, Snow Brand Milk Products Co., Ltd, Shimotsuga-gun, Tochigi, Japan
  • Yoshiji Yamada
    Department of Geriatric Research, National Institute for Longevity Sciences, Obu, Aichi, Japan

Abstract

<jats:title>Abstract</jats:title> <jats:p>Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) is a soluble member of the tumor necrosis factor receptor family of proteins and plays an important role in the negative regulation of osteoclastic bone resorption. Whether OPG/OCIF circulates in human blood and how its level changes under pathological conditions is not known. To address these issues, a panel of monoclonal antibodies was generated against recombinant OPG/OCIF and screened for reactivity with solid-phase monomeric and homodimeric forms of the recombinant protein. Antibodies that showed high affinity for both forms of OPG/OCIF and those that selectively recognized the homodimer were identified, enabling development of two types of sensitive enzyme-linked immunosorbent assay (ELISA): one that detects both forms of OPG/OCIF equally and one specific for the homodimer. Characterization of circulating OPG/OCIF with these ELISAs revealed that the protein exists in human serum mainly in the monomeric form. The serum concentration of OPG/OCIF increased with age in both healthy Japanese men and women, and was significantly higher in postmenopausal 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 increased in those postmenopausal women with a high rate of bone turnover, as determined by increased serum bone-specific alkaline phosphatase and urinary 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 response to enhanced osteoclastic bone resorption and the resultant bone loss rather than a cause of osteoporosis.</jats:p>

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