Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin.
Alterations of human skin connective tissue structure and function are prominent features of chronological aging and solar UV irradiation-induced premature aging (photoaging). These skin connective tissue abnormalities result, in part, from reduced synthesis and elevated degradation of type I collagen, the major structural protein in skin. Here, we report that cysteine-rich 61 (CYR61/CCN1), a novel mediator of collagen homeostasis, is predominantly expressed in human skin connective tissue and is significantly elevated in fibroblasts in chronologically aged (80+ years) and photoaged human skin in vivo. In cultured human skin fibroblasts, elevated CYR61 expression substantially reduces type I procollagen and concurrently increases matrix metalloproteinase-1 (MMP-1), which initiates fibrillar collagen degradation. Elevated CYR61 caused down-regulation of transforming growth factor-beta type II receptor mRNA and protein levels, thereby impairing the transforming growth factor-beta pathway, which reduced type I procollagen and raised MMP-1 expression. Furthermore, elevated CYR61 induced transcription factor activator protein-1 (AP-1), which functions to stimulate MMP-1 expression. Thus, elevated expression of CYR61 in human skin fibroblasts acts through multiple pathways to cause alterations of collagen homeostasis similar to those pathways observed in aged human skin in vivo. These data identify CYR61 as a pivotal regulator of collagen production and degradation in aged and photoaged human skin.
Quan
Taihao
T
Department of Dermatology, University of Michigan Medical School, 1150 W. Medical Center Dr., Medical Science I, Room 6447, Ann Arbor, Michigan 48109-0609, USA.
He
Tianyuan
T
Shao
Yuan
Y
Lin
Lin
L
Kang
Sewon
S
Voorhees
John J
JJ
Fisher
Gary J
GJ
D000328:Adult; D000369:Aged, 80 and over; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003238:Connective Tissue / Q000378:metabolism; D055515:Cysteine-Rich Protein 61; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006706:Homeostasis; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015595:Skin Aging; D013473:Sunscreening Agents / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
C501848:CCN1 protein, human; D024042:Collagen Type I; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D013473:Sunscreening Agents; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020781:Matrix Metalloproteinase 1