A CHEMICALLY-MODIFIED TETRACYCLINE INHIBITS STREPTOZOTOCIN-INDUCED DIABETIC DEPRESSION OF SKIN COLLAGEN-SYNTHESIS AND STEADY-STATE TYPE-I PROCOLLAGEN MESSENGER-RNA

Wasting of connective tissues including skin, bone, and cartilage have been closely associated with elevated matrix metalloproteinase (MMP) activity and depressed collagen content in the streptozotocin (STZ)-in duced diabetic rat, while tetracyclines have been reported to normaliz e total body weight, skin hydroxyproline and collagen content in this model, in part through inhibition of MMPs. In the present study, we re port the effect of CMT-1, a chemically modified tetracycline that lack s antimicrobial properties but retains divalent cation binging and MMP inhibitory activity, on diabetic skin collagen synthesis and steady-s tate levels of procollagen alpha 1(I) mRNA. Male, 4-month old Sprague- Dawley rats received a single injection of 75 mg/kg STZ or citrate veh icle alone and diabetic status was confirmed by positive glucosuria. S ome diabetic animals received 10 mg/day of CMT-1 by oral gavage and, 2 8 days after STZ treatment, body weight, blood glucose values and the in vivo rates of skin collagen production were measured using the pool -expansion technique. Steady-state levels of procollagen alpha 1(I) mR NA were analyzed 21 days after STZ treatment by hybridization of total RNA with a P-32 labelled cDNA to rat type I procollagen alpha 1(I) mR NA in a dot-blot assay. STZ treatment was bound to significantly depre ss body weight, skin collagen hydroxyproline content, the in vivo rate of collagen production, and hybridizable levels of type I procollagen alpha 1(I) mRNA. CMT-1 administered daily to STZ-treated rats inhibit ed the diabetic depression of these parameters but had little or no ef fect on non-diabetic controls or on STZ-induced hyperglycemia, Thus, i n addition to the inhibition of MMP mediated extracellular collagen de gradation, these results suggest CMT-1 also acts to inhibit diabetic c onnective tissue breakdown in STZ-induced diabetes by increasing both steady-state levels of type I procollagen mRNA and collagen synthesis through mechanism(s) that are independent of the antibacterial propert ies of tetracyclines. (C) 1998 Elsevier Science B.V.