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Molecular mechanisms of human skin natural aging and photoaging (Molecular mechanisms by which aging adversely affects skin connective tissue)

Gary Fisher, PhD and Tai Hao Quan, PhD

The TGF-β pathway is the major regulator of extracellular matrix production in human skin connective tissue. Impairment of TGF-β function results in reduced production of collagen, the leading cause of thin fragile skin and compromised wound healing, observed in aged human skin. We have demonstrated that impairment of the TGF-β pathway is caused primarily by down regulation of the type II TGF-β receptor via reduced gene transcription. Currently we are investigating mechanisms of age-related alterations of human skin connective tissue through impairment of the TGF-β pathway.

The Photobiology Resarch Program is seeking to understand the molecular mechanisms responsible for loss of type I procollagen synthesis in chronologically aged and photoaged human skin. Type I collagen is the major structural protein in human skin, providing skin with strength and resiliency. Type I collagen is synthesized in a precursor form, type I procollagen, by fibroblasts that reside in skin connective tissue. As skin ages, as a consequence of either the passage of time, or chronic exposure to ultraviolet (UV) irradiation from the sun (photoaging), type I procollagen synthesis declines. This loss of type I procollagen is a major contributing factor to thinning and increased fragility of naturally aged skin, and the old wrinkled appearance of photoaged skin.

The mechanism responsible for loss of type I procollagen production in naturally aged and photoaged human skin is not known. The major regulator of type I procollagen synthesis is the transforming growth factor-beta (TGF-β)/Smad pathway. Evidence indicates that TGF-β regulates procollagen production both directly and indirectly, via TGF-β regulated connective tissue growth factor (CTGF). UV irradiation impairs the TGF-β/Smad pathway, and this impairment is associated with reduced CTGF expression and reduced type I procollagen synthesis in human skin in vivo and human skin fibroblasts in vitro. Inhibition of the TGF-β/Smad pathway by UV irradiation occurs primarily as a consequence of down-regulation of the TGF-β receptor type II.

Our research is testing the hypothesis that the TGF-β/Smad pathway is impaired in naturally aged and photoaged human skin, and that this impairment contributes to loss of type I procollagen synthesis. The specific aims of our work are to :

  1. Characterize TGF-β/SMAD signaling pathway in chronologically aged versus young human skin in vivo,
  2. Characterize TGF-β/SMAD signaling pathway in photoaged versus non-photoaged human skin in vivo,
  3. Determine the mechanisms by which UV inhibits TGF-β type II receptor gene expression in human skin fibroblasts, and
  4. Determine the role of CTGF in reduced procollagen in aged and photoaged human skin and the mechanism by which CTGF regulates procollagen production in human skin fibroblasts.

Through this work we are providing important new insights into modalities for treatment and prevention of age-related loss of skin strength and resiliency.

GRANT NUMBER: 5R01AG019364-04
ICD: NATIONAL INSTITUTE ON AGING
IRG: GMA

References:

  1. Quan T, He T, Voorhees JJ, Fisher GJ. Ultraviolet irradiation induces Smad7 via induction of transcription factor AP-1 in skin fibroblasts. J Biol Chem. 2005;280:8079-8085.
  2. Quan T, He TY, Kang S, Voorhees JJ, Fisher GJ. Solar UV irradiation reduces collagen in photoaged human skin by blocking TGF-β type II receptor/SMAD signaling. Amer J Pathol. 2004;165:741-751.
  3. Quan T, He TY, Kang S, Voorhees JJ, Fisher GJ. Ultraviolet irradiation alters transforming growth factor-β/Smad pathway in human skin in vivo. J Invest Dermatol. 2002;119(2):499-506.
  4. Quan T, He T, Kang S, Voorhees JJ, Fisher GJ. Connective tissue growth factor (CTGF): Expression in human skin in vivo and inhibition by ultraviolet irradiation. J Invest Dermatol. 2002;118(3):402-408.

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