Studies of the effects of 1,25-dihydroxyvitamin D on skeletal and calcium homeostasis and on inhibition of tumor cell growth

Vitamin D, parathyroid hormone (PTH), and parathyroid hormone-related pepti de (PTHrP) are major regulators of calcium metabolism and vitamin D can als o reduce the growth of normal cells and tumor cells. PTHrP and PTH act via a common membrane receptor (PTHR). The mouse PTHR is regulated by a kidney- selective upstream promoter P-1 and ubiquitous downstream promoter P-2. In vitro and in vivo; 1,25(OH)(2)D can inhibit PTHR expression in bone but not cartilage by downregulating transcription via P-2. Gene transcription of P THrP per se can also be downregulated by 1,25(OH)(2)D and by low calcemic v itamin D analogs. This inhibitory effect may reduce the hypercalcemia cause d by overproduction of PTHrP by tumor cells. In a malignant keratinoctye ce ll line, phosphorylation of the retinoid X receptor alpha occurs through th e activated Ras-MAP kinase pathway and results in attenuated trans-activati on by the vitamin D receptor, its heterodimeric partner. This decreases the growth-inhibitory efficacy of 1,25(OH)(2)D. Studies of the capacity of vit amin D to alter PTHrP production and action and of its anti-proliferative e ffects can, therefore, shed important light on basic mechanisms controlling these events, and may also have major implications for clinical medicine a nd therapeutics. (C) 2001 Elsevier Science Ltd. All rights reserved.