Yasuo Imanishi1, Masaaki Inaba, Takehisa Kawata, Yoshiki Nishizawa. 1. Osaka City University Graduate School of Medicine, Metabolism, Endocrinology and Molecular Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545 8585, Japan +81 6 6645 3806 ; +81 6 6645 3808 ; imanishi@med.osaka-cu.ac.jp.
Abstract
BACKGROUND: Disorders of mineral and bone metabolism have been implicated as a risk factor in the high mortality in patients with chronic kidney disease (CKD). Hyperphosphatemia, disorders of vitamin D metabolism and secondary hyperparathyroidism of uremia (SHPT) are therapeutic targets in these patients to improve the mortality. Animal models for CKD are indispensable and uremic rats produced by 5/6-nephrectomies are one of the most useful animal models for the development of new therapeutic agents. As there are limitations of uremic rats such as short lifespan and less severity of secondary hyperparathyroidism distinct from CKD patients on maintenance hemodialysis, the development of new model animals is expected. OBJECTIVE: This review discusses the molecular pathogenesis of hyperfunctioning parathyroid diseases and the applications of animal models exhibiting hyperparathyroidisms in the aspect of the development of new therapeutics. CONCLUSION: PTH-cyclin D1 transgenic mice, with parathyroid-targeted overexpression of cyclin D1 oncogene, not only developed abnormal parathyroid cell proliferation but, notably, also developed biochemical hyperparathyroidism with characteristic abnormalities in bone. The mice exhibit age-dependent development of biochemical hyperparathyroidism, which enables testing of the drug precisely. In addition, the mice develop parathyroid cell hyperplasia, followed by monoclonal expansion, which is observed in refractory SHPT patients.
BACKGROUND: Disorders of mineral and bone metabolism have been implicated as a risk factor in the high mortality in patients with chronic kidney disease (CKD). Hyperphosphatemia, disorders of vitamin D metabolism and secondary hyperparathyroidism of uremia (SHPT) are therapeutic targets in these patients to improve the mortality. Animal models for CKD are indispensable and uremic rats produced by 5/6-nephrectomies are one of the most useful animal models for the development of new therapeutic agents. As there are limitations of uremic rats such as short lifespan and less severity of secondary hyperparathyroidism distinct from CKDpatients on maintenance hemodialysis, the development of new model animals is expected. OBJECTIVE: This review discusses the molecular pathogenesis of hyperfunctioning parathyroid diseases and the applications of animal models exhibiting hyperparathyroidisms in the aspect of the development of new therapeutics. CONCLUSION:PTH-cyclin D1transgenic mice, with parathyroid-targeted overexpression of cyclin D1 oncogene, not only developed abnormal parathyroid cell proliferation but, notably, also developed biochemical hyperparathyroidism with characteristic abnormalities in bone. The mice exhibit age-dependent development of biochemical hyperparathyroidism, which enables testing of the drug precisely. In addition, the mice develop parathyroid cell hyperplasia, followed by monoclonal expansion, which is observed in refractory SHPT patients.