1,25-DIHYDROXY-VITAMIN-D-3 INHIBITS ADIPOCYTE DIFFERENTIATION AND GENE-EXPRESSION IN MURINE BONE-MARROW STROMAL CELL CLONES AND PRIMARY CULTURES

Bone marrow stromal stem cells differentiate into adipocytes and osteo blasts. These two Lineages are thought to be reciprocally related, in part due to the observation that the osteoblast-inducing factor, 1,25 dihydroxy vitamin D-3 [1,25(OH)(2)D-3], inhibited adipogenesis of rat femoral-derived stromal cell cultures. However, the literature is divi ded concerning the adipogenic effects of this steroid hormone. This wo rk examined the effect of 1,25(OH)(2)D-3 (10(-12)-10(-8) M) On murine femoral-derived bone marrow stromal cell differentiation in response t o adipogenic agonists employing two different classes of nuclear hormo ne receptors: the glucocorticoid receptor (hydrocortisone) or peroxiso me proliferator-activated receptors (thiazolidinediones). Experiments used the multipotent murine bone marrow stromal cell line, BMS2, and i ts subclones, as well as primary-derived murine hone marrow stromal ce ll cultures. In all systems examined, 1,25(OH)(2)D-3 blocked adipogene sis induced by hydrocortisone, methylisobutylxanthine, and indomethaci n based on flow cytometric analysis of lipid accumulation. This correl ated with reduced messenger RNA levels of the late adipocyte gene mark ers, aP2 and adipsin. In the BMS2 subclone no. 24, the 1,25(OH)(2)D-3 actions were concentration dependent, Whereas 1,25(OH)(2)D-3 partially inhibited thiazolidinedione-induced adipogenesis in the parental BMS2 cell line, it had minimal effect on the thiazolidinediane-induced dif ferentiation of the BMS2 subclone and primary cultures. These findings indicate that 1,25(OH)(2)D-3, at nanomolar concentrations, completely inhibits murine bone marrow stromal cell differentiation in response to glucocorticoid-based adipogenic agonists but is a less effective ad ipogenic antagonist following induction with thiazolidinediones. This work supports the conclusion that 1,25(OH)(2)D-3 inhibits murine femor al-derived bone marrow stromal cell adipogenesis.