title: Molecular basis of the alteration in skin collagen metabolism in response to in vivo dexamethasone treatment: effects on the synthesis of collagen type I and III, collagenase, and tissue inhibitors of metalloproteinases.
abstract: BACKGROUND
  Glucocorticoids are widely used for the treatment of various diseases, despite known side-effects such as skin atrophy. Many studies have shown that the status of collagen fibres in the skin is affected by glucocorticoid treatment. However, the molecular mechanism underlying the alteration of collagen metabolism in the skin by glucocorticoid treatment remains unknown.
  
  
  OBJECTIVE
  To characterize the molecular mechanisms related to the deterioration of the dermis in response to glucocorticoids, the status of two major types of collagen, collagenase, and tissue inhibitors of metalloproteinases (TIMPs) in the dorsal skin of rats was studied at the protein and mRNA levels.
  
  
  METHODS
  Samples of rat dorsal skin were obtained after daily (1 mg kg-1) subcutaneous injections of dexamethasone (DEX) for 8 days. mRNA levels of two types of collagen and of TIMPs were measured by a lysate RNase protection assay. mRNA levels of collagenase were measured by a quantitative polymerase chain reaction. Protein levels of collagen and collagenase were measured by an immunoblot analysis.
  
  
  RESULTS
  Levels of type I tropocollagen and type III tropocollagen were drastically reduced in response to DEX. The effects of DEX treatment were more severe on type III than type I collagen: it also produced a significant decrease in fibril collagen of type III collagen. DEX treatment was found to decrease both active and latent forms of collagenase as well as its mRNA levels. Among TIMPs, mRNA levels of TIMP-1 and TIMP-2 were decreased in response to DEX treatment, whereas those of TIMP-3 were not affected.
  
  
  CONCLUSIONS
  These results suggest that DEX treatment strongly interferes with both the synthesis and degradation of type I collagen and, more drastically, type III collagen, the molecule that is known to play a major role in the initiation of wound healing. The present study may provide a molecular basis for the deterioration of skin function, impaired wound healing, and skin atrophy caused by glucocorticoid treatment.
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, Tokyo University, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Oishi
authors.forename: Z W
authors.initials: ZW
authors.lastname: Fu
authors.forename: Y
authors.initials: Y
authors.lastname: Ohnuki
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis*; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D024042:Collagen Type I; D024043:Collagen Type II; D005938:Glucocorticoids; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D003907:Dexamethasone; D003094:Collagen; D017364:Collagenases