Molecular basis of hyperparathyroidism and potential targets for drug development.
Our appreciation of the molecular pathogenesis of primary hyperparathyroidism (HPT) has seen great advances over the past decade. This improved understanding may well lead to the development of new treatment options that are specifically targeted to defective pathways. This review summarizes recent advances in the molecular basis of HPT and associated endocrinopathies, and discusses the potential for these and future findings to provide targets for alternative approaches to therapy. The only proven contributors to common sporadic HPT, by virtue of clonal genetic abnormalities, are the cyclin D1 and MEN1 genes. Cyclin D1 is an oncogene that encodes a key regulator of the cell cycle, while MEN1 is a tumor suppressor gene that has also been implicated in familial multiple endocrine neoplasia type 1 (MEN1), in which primary HPT is common. In addition, other key parathyroid regulatory pathways may play a role in HPT pathogenesis. 1,25 (OH)2-vitamin D. Ca2+ and phosphate are regarded as principal regulators of parathyroid cell proliferation and PTH secretion. Therefore, prime candidate targets include the Ca2+ sensing receptor (CASR) gene, the vitamin D receptor (VDR) gene, a putative phosphate receptor gene, their cognate gene products, and other genes or proteins involved in their respective biochemical pathways. Attempts to identify new therapies based specifically on the defective pathways in HPT could complement or eventually supplant traditional approaches.
Krebs
L J
LJ
Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3101, USA. Krebs@up.uchc.edu
Arnold
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D016147:Genes, Tumor Suppressor; D019940:Genes, bcl-1; D006801:Humans; D006961:Hyperparathyroidism / Q000188:drug therapy* / Q000235:genetics*; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D010281:Parathyroid Hormone / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000502:physiology; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology
D010281:Parathyroid Hormone; D010710:Phosphates; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D019938:Cyclin D1; D002118:Calcium