Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL), frequently associated with hypercalcemia and bone destruction. A positive correlation between the appearance of an antibody recognizing the central region (Asp197 to Leu216) on Gp46, gp46-197, and the severity of ATL has been demonstrated. In this study, five male Nihon Hakusyoku rabbits were immunized with a synthetic peptide corresponding to the gp46-197 region to clarify its action and mechanism. Two of the rabbits showed piloerection, anorexia, and somnolence, and died soon after booster administration. The serum calcium level of the dead rabbits was significantly high, compared to those of surviving rabbits. Interestingly, amino acid sequences homologous with gp46-197 were found in the carboxylterminal half of osteoprotegerin (OPG), an osteoclast inhibitory factor. To confirm the effect of the gp46-197 region on osteogenesis in vivo, the peptide was intraperitoneally administered to male Sprague-Dawley rats. The administration of the gp46-197 peptide resulted in a decrease of bone mineral density (BMD), a significant increase of serum calcium level, and inhibition of normal bone growth in both short-and long-term experiments. In rats, femoral growth inhibition by the gp46- A dult T-cell leukemia (ATL), a malignancy of helper/inducer T lymphocytes, is associated with human T-cell leukemia virus type-1 (HTLV-1) infection.(1) ATL clinically shows hypercalcemia and lytic bone lesions in high prevalence, (2) which are known to be mediated by parathyroid hormone-related protein (PTHrP) and lymphokines, such as interleukin 1 (IL-1), IL-6, and macrophage inflammatory protein-1α.(3,4) Several reports revealed that severe combined immunodeficient/beige mice inoculated with a human ATL line developed lymphoma with hypercalcemia, and plasma PTHrP concentrations were markedly increased in mice with lymphoma.(5,6) About 70% of ATL patients show a high serum calcium level throughout the clinical course, particularly in the aggressive stage.(7) It was reported that the overexpression of the receptor activator of the nuclear factor-κB ligand (RANKL) gene is correlated with hypercalcemia in ATL, (8) and it is well known that bisphosphonate is efficient in the treatment of hypercalcemia in ATL patients. RANKL promotes the differentiation and proliferation of osteoclasts. Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) receptor superfamily, acts as a decoy receptor for RANKL and neutralizes the effect of RANKL in osteogenesis.(9) Both the gene expression and the protein production of OPG were reported to be stimulated by 17β-estradiol (E 2 ), (10,11) and there was a positive relationship between OPG and serum E 2 level.(12) OPG-overexpressing mice are osteopetrotic, (9) whereas OPG-deficient mice are osteoporotic.Therefore, OPG is known to play a pivotal role in regulating bone mass. In vitro, OPG inhibits osteoclastogenesis, (9,14) blocks bone resorption by mature osteoclasts, (15,16) and promotes apoptosis of osteoclas...