title: All-trans-retinoic acid suppresses matrix metalloproteinase activity and increases collagen synthesis in diabetic human skin in organ culture.
abstract: Diabetes increases susceptibility to chronic skin ulceration. The etiology of chronic wound formation in diabetic individuals is multifactoral but may be accelerated by changes in the structure and function of the skin secondary to impaired fibroblast proliferation, decreased collagen synthesis, and increased matrix metalloproteinase (MMP) expression. This study explored the effects of all-trans-retinoic acid (RA) on cellular and biochemical features of diabetic human skin in organ culture. Two-mm skin biopsies from hip or ankle were obtained from diabetic subjects and incubated for 9 days in the absence or presence of 2 micro mol/L RA. Hip skin from non-diabetic individuals served as control. Following organ culture incubation, untreated and RA-treated tissue was examined histologically after staining with hematoxylin and eosin. In parallel, organ culture-conditioned medium collected on days 5 and 7 was assayed for levels of active and total MMP-1 (interstitial collagenase) and MMP-9 (gelatinase B). The same organ culture fluids were assayed for the presence of soluble collagen. In comparison with skin from non-diabetic individuals, diabetic skin demonstrated no major differences in overall epidermal thickness or collagen production (both were increased in RA-treated tissue as compared to non-RA-treated tissue). In contrast, levels of MMP-9 (active forms) were elevated in organ culture fluid from diabetic skin as compared to non-diabetic control skin. In the presence of RA, active forms of both MMP-1 and MMP-9 were reduced. Together, these data suggest that RA has the capacity to improve structure and function of diabetic skin, and that a major effect is on reduction of collagen-degrading MMPs.
authors.affiliation: Department of Pathology, The University of Michigan, 1301 Catherine Road, Ann Arbor, MI 48109, USA.
authors.forename: Humaira
authors.initials: H
authors.lastname: Lateef
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stevens
authors.forename: James
authors.initials: J
authors.lastname: Varani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003094:Collagen / Q000096:biosynthesis* / Q000187:drug effects; D017364:Collagenases / Q000032:analysis; D017077:Culture Media, Conditioned / Q000032:analysis / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000378:metabolism; D004792:Enzyme Precursors / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D009924:Organ Culture Techniques; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D017077:Culture Media, Conditioned; D004792:Enzyme Precursors; D019715:Tissue Inhibitor of Metalloproteinase-1; D014212:Tretinoin; D003094:Collagen; D017364:Collagenases; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1