Fibroblast heterogeneity in collagenolytic response to colchicine

Abstract

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in various physiological and pathological conditions, including those that involve homeostasis of collagen. Drug induced regulation of MMP-1, other MMPs and TIMPs is critical in treatment of various diseases, e.g. the use of the plant alkaloid, colchicine. One possible factor that might explain the failure in colchicine-treatment of some patients is interindividual variability on the cellular level. To investigate the possible individual heterogeneity in response to colchicine, we studied the effect of colchicine-induced synthesis of collagenase from 32 different human skin fibroblast strains derived from both healthy individuals as well as individuals with different skin diseases. We showed that colchicine induced an increased synthesis of collagenase in 22 of 32 cases. This heterogeneity occurred in fibroblasts from healthy as well as diseased individuals. To determine if colchicine also affected the fibroblast synthesis of gelatinase, stromelysin and tissue inhibitors of MMPs, we investigated several individuals from a single family. The results showed that both colchicine responsive and non-responsive fibroblasts with respect to collagenase synthesis responded to colchicine by an increased stromelysin synthesis, while the synthesis of gelatinase and TIMP-1 were unaffected. As a whole, our results indicate that individual heterogeneity in collagenase response to colchicine treatment may partly explain some of the controversial results obtained with colchicine as a drug.