Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smad signaling

Am J Pathol. 2004 Sep;165(3):741-51. doi: 10.1016/s0002-9440(10)63337-8.

Abstract

Ultraviolet (UV) irradiation from the sun reduces production of type I procollagen (COLI), the major structural protein in human skin. This reduction is a key feature of the pathophysiology of premature skin aging (photoaging). Photoaging is the most common form of skin damage and is associated with skin carcinoma. TGF-beta/Smad pathway is the major regulator of type I procollagen synthesis in human skin. We have previously reported that UV irradiation impairs transforming growth factor-beta (TGF-beta)/Smad signaling in mink lung epithelial cells. We have investigated the mechanism of UV irradiation impairment of the TGF-beta/Smad pathway and the impact of this impairment on type I procollagen production in human skin fibroblasts, the major collagen-producing cells in skin. We report here that UV irradiation impairs TGF-beta/Smad pathway in human skin by down-regulation of TGF-beta type II receptor (TbetaRII). This loss of TbetaRII occurs within 8 hours after UV irradiation and precedes down-regulation of type I procollagen expression in human skin in vivo. In human skin fibroblasts, UV-induced TbetaRII down-regulation is mediated by transcriptional repression and results in 90% reduction of specific, cell-surface binding of TGF-beta. This loss of TbetaRII prevents downstream activation of Smad2/3 by TGF-beta, thereby reducing expression of type I procollagen. Preventing loss of TbetaRII by overexpression protects against UV inhibition of type I procollagen gene expression in human skin fibroblasts. UV-induced down-regulation of TbetaRII, with attendant reduction of type I procollagen production, is a critical molecular mechanism in the pathophysiology of photoaging.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Collagen Type I / genetics
  • Collagen Type I / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Fibroblasts / physiology
  • Fibroblasts / radiation effects*
  • Humans
  • Luciferases / metabolism
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Skin / metabolism
  • Skin / radiation effects*
  • Skin Aging*
  • Smad Proteins
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • Ultraviolet Rays

Substances

  • Collagen Type I
  • DNA-Binding Proteins
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • TGFB1 protein, human
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Luciferases
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II