Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin d1 in transgenic mice

Yasuo Imanishi, Yoshitaka Hosokawa, Katsuhiko Yoshimoto, Ernestina Schipani, Sanjay Mallya, Alexandros Papanikolaou, Olga Kifor, Takehiko Tokura, Marilyn Sablosky, Felicia Ledgard, Gloria Gronowicz, Timothy C. Wang, Emmett V. Schmidt, Charles Hall, Edward M. Brown, Roderick Bronson, Andrew Arnold

Research output: Contribution to journalArticle

168 Scopus citations

Abstract

The relationship between abnormal cell proliferation and aberrant control of hormonal secretion is a fundamental and poorly understood issue in endocrine cell neoplasia. Transgenic mice with parathyroid-targeted overexpression of the cyclin D1 oncogene, modeling a gene rearrangement found in human tumors, were created to determine whether a primary defect in this cell-cycle regulator can cause an abnormal relationship between serum calcium and parathyroid hormone response, as is typical of human primary hyperparathyroidism. We also sought to develop an animal model of hyperparathyroidism and to examine directly cyclin D1's role in parathyroid tumorigenesis. Parathyroid hormone gene regulatory region-cyclin D1 (PTH-cyclin D1) mice not only developed abnormal parathyroid cell proliferation, but also developed chronic biochemical hyperparathyroidism with characteristic abnormalities in bone and, notably, a shift in the relationship between serum calcium and PTH. Thus, this animal model of human primary hyperparathyroidism provides direct experimental evidence that overexpression of the cycIin D1 oncogene can drive excessive parathyroid cell0 proliferation and thai this proliferative defect need not occur solely as a downstream consequence of a defect in parathyroid hormone secretory control by serum calcium, as had been hypothesized. Instead, primary deregulation of cell-growth pathways can cause both the hypercellularity and abnormal control of hormonal secretion thai are almost inevitably linked together in this common disorder.

Original languageEnglish (US)
Pages (from-to)1093-1102
Number of pages10
JournalJournal of Clinical Investigation
Volume107
Issue number9
DOIs
StatePublished - Jan 1 2001
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Imanishi, Y., Hosokawa, Y., Yoshimoto, K., Schipani, E., Mallya, S., Papanikolaou, A., Kifor, O., Tokura, T., Sablosky, M., Ledgard, F., Gronowicz, G., Wang, T. C., Schmidt, E. V., Hall, C., Brown, E. M., Bronson, R., & Arnold, A. (2001). Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin d1 in transgenic mice. Journal of Clinical Investigation, 107(9), 1093-1102. https://doi.org/10.1172/JCI10523