Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice

The relationship between abnormal cell proliferation and aberrant control o f hormonal secretion is a fundamental and poorly understood issue in endocr ine cell neoplasia. Transgenic mice with parathyroid-targeted overexpressio n of the cyclin D1 oncogene, modeling a gene rearrangement found in human t umors, were created to determine whether a primary defect in this cell-cycl e regulator can cause an abnormal relationship between serum calcium and pa rathyroid hormone response, as is typical of human primary hyperparathyroid ism. We also sought to develop an animal model of hyperparathyroidism and t o examine directly cyclin Dl's role in parathyroid tumorigenesis, Parathyro id hormone gene regulatory region-cyclin D1 (PTH-cyclin D1) mice not only d eveloped abnormal parathyroid cell proliferation, but also developed chroni c biochemical hyperparathyroidism with characteristic abnormalities in bone and, notably, a shift in the relationship between serum calcium and PTH, T hus, this animal model of human primary hyperparathyroidism provides direct experimental evidence that overexpression of the cyclin D1 oncogene can dr ive excessive parathyroid cell proliferation and that this proliferative de fect need not occur solely as a downstream consequence of a defect in parat hyroid hormone secretory control by serum calcium, as had been hypothesized . Instead, primary deregulation of cell-growth pathways carl cause both the hypercellularity and abnormal control of hormonal secretion that are almos t inevitably linked together in this common disorder.