1 alpha,25-dihydroxyvitamin D-3 rapidly inhibits fibroblast-induced collagen gel contraction

1 alpha a,25-Dihydroxyvitamin D-3 (1,25-D-3) inhibits the proliferation of fibroblasts in vitro in monolayer culture, We investigated the effect of 1,25-D-3 on normal murine and human fibroblasts cultured in collagen type I gels, which more closely resembles the in vivo situation in the dermis, In this culture system 1,25-D-3 had no effect on fibroblast proliferation; however, the fibroblast-induced collagen gel contraction was inhibited in a time- and concentration-dependent manner in the nanomolar concentration range. 25-Hydroxyvitamin D-3 and 24,25-dihydroxyvitamin D-3 were inactive, 1,25-D-3 had no effect in fibroblasts lacking a functional vitamin D receptor, Pretreatment of fibroblasts in monolayer culture for 5 min was sufficient to trigger the inhibition of collagen gel contraction, Nifedipine increased collagen gel contraction and counteracted the effect of 1,25-D-3. The inhibition of collagen gel contraction by 1,25-D-3 is supposed to be mediated by the vitamin D receptor because a functional vitamin D receptor is required, and vitamin D metabolites with low affinity to the vitamin D receptor were inactive, Brief pretreatment of fibroblasts was sufficient to trigger the inhibitory effect of 1,25-D-3, suggesting a nongenomic effect. A genomic mode of action could not be ruled out, however, because the inhibition was first measured after 24 h. The antagonism of the calcium channel antagonist nifedipine probably represents the sum of two opposite effects rather than supporting evidence for a nongenomic mode of action of 1,25-D-3. In conclusion, 1,25-D-3 has a specific and rapidly triggered inhibitory effect on fibroblast-induced collagen gel contraction.