Effects of calcitriol and its analogues, calcipotriol (MC 903) and 20-Epi-1α,25-dihydroxyvitamin D 3 (MC 1288), on calcium influx and DNA synthesis in cultured muscle cells

Abstract

The fast actions of the secosteroid hormone 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2D 3; calcitriolJ and the synthetic analogues calcipotriol (MC 903) and 20-epi-1α,25(OH) 2D 3 (MC 1288) on cell calcium influx were compared in rat duodenum enterocytes as well as in cells from chick embryo skeletal muscle (myoblasts) and heart (myocytes), at various concentrations (10 −12 to 10 −8 M) and treatment intervals (1–10 min). In enterocytes, at a concentration of 10 −11 M, MC 1288 was significantly more active than 1,25(OH) 2D 3 in rapidly stimulating 45Ca 2+ uptake by enterocytes (80 vs 38% above controls, respectively), whereas MC 903 was devoid of activity. However, calcipotriol increased Ca 2+ influx in myocytes and myoblasts to a greater extent than the natural hormone, whereas MC 1288 was more active only in myoblasts. Analogously to 1,25(OH) 2D 3, the fast MC 903- and MC 1288-induced stimulation of 45Ca 2+ uptake in enterocytes and muscle cells could be blocked by both verapamil and nifedipine. In addition, MC 903 and MC 1288 were more effective than 1,25(OH) 2D 3 in stimulating DNA synthesis in proliferating myoblasts and in inhibiting DNA synthesis in differentiating myoblasts. The results suggest, therefore, that modifications in the side-chain of the 1,25(OH) 2D 3 molecule increase its ability to modulate muscle cell Ca 2+ metabolism and growth. These findings are potentially relevant for the development of analogues for the treatment of vitamin D-dependent myopathies.