title: Retinoids suppress cysteine-rich protein 61 (CCN1), a negative regulator of collagen homeostasis, in skin equivalent cultures and aged human skin in vivo.
abstract: Alterations in connective tissue collagen are prominent features of both chronologically aged and photoaged (ageing because of sun exposure) human skin. These age-related abnormalities are mediated in part by cysteine-rich protein 61 (CCN1). CCN1 is elevated in the dermis of both chronologically aged and photoaged human skin in vivo and promotes aberrant collagen homeostasis by down-regulating type I collagen, the major structural protein in skin, and promoting collagen degradation. Vitamin A and its metabolites have been shown to improve chronologically aged and photoaged skin by promoting deposition of new collagen and preventing its degradation. Here, we investigated regulation of CCN1 expression by retinoids in skin equivalent cultures and chronologically aged and photoaged human skin in vivo. In skin equivalent cultures, all-trans retinoic acid (RA), the major bioactive form of vitamin A in skin, significantly increased type I procollagen and reduced collagenase (matrix metalloproteinases-1, MMP-1). Addition of recombinant human CCN1 to skin equivalent cultures significantly reduced type I procollagen and increased MMP-1. Importantly, RA significantly reduced CCN1 expression in skin equivalent cultures. Topical treatment with retinol (vitamin A, 0.4%) for 7days significantly reduced CCN1 mRNA and protein expression in both chronologically aged (80+years) and photoaged human skin in vivo, compared to vehicle-treated skin. These data indicate that the mechanism by which retinoids improve aged skin, through increased collagen production, involves down-regulation of CCN1.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109-5609, USA.
authors.forename: Taihao
authors.initials: T
authors.lastname: Quan
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Qin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shao
authors.forename: Yiru
authors.initials: Y
authors.lastname: Xu
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015536:Down-Regulation / Q000235:genetics; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D018625:Microscopy, Atomic Force; D008875:Middle Aged; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015595:Skin Aging / Q000187:drug effects* / Q000502:physiology; D013499:Surface Properties; D023822:Tissue Engineering / Q000379:methods; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000008:administration & dosage / Q000494:pharmacology; D055815:Young Adult
chemical_list: C501848:CCN1 protein, human; D024042:Collagen Type I; D055515:Cysteine-Rich Protein 61; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D012176:Retinoids; C082928:retinoic acid binding protein II, cellular; D014801:Vitamin A; D014212:Tretinoin; D020781:Matrix Metalloproteinase 1