title: Age-Associated Increase in Skin Fibroblast-Derived Prostaglandin E2 Contributes to Reduced Collagen Levels in Elderly Human Skin.
abstract: Production of type I collagen declines during aging, leading to skin thinning and impaired function. Prostaglandin E2 (PGE2) is a pleiotropic lipid mediator that is synthesized from arachidonic acid by the sequential actions of cyclooxygenases (COX) and PGE synthases (PTGES). PGE2 inhibits collagen production by fibroblasts in vitro. We report that PTGES1 and COX2 progressively increase with aging in sun-protected human skin. PTGES1 and COX2 mRNA were increased 3.4-fold and 2.7-fold, respectively, in the dermis of elderly (>80 years) versus young (21-30 years) individuals. Fibroblasts were the major cell source of both enzymes. PGE2 levels were increased 70% in elderly skin. Fibroblasts in aged skin display reduced spreading due to collagen fibril fragmentation. To investigate the relationship between spreading and PGE2 synthesis, fibroblasts were cultured on micropost arrays or hydrogels of varying mechanical compliance. Reduced spreading/mechanical force resulted in increased expression of both PTGES1 and COX2 and elevated levels of PGE2. Inhibition of PGE2 synthesis by diclofenac enhanced collagen production in skin organ cultures. These data suggest that reduced spreading/mechanical force of fibroblasts in aged skin elevates PGE2 production, contributing to reduced collagen production. Inhibition of PGE2 production may be therapeutically beneficial for combating age-associated collagen deficit in human skin.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Lei
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Shinuo
authors.initials: S
authors.lastname: Weng
authors.affiliation: Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Christal A
authors.initials: CA
authors.lastname: Worthen
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Toru
authors.initials: T
authors.lastname: Okubo
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnston
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA. Electronic address: gjfisher@med.umich.edu.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
mesh_terms: D000328:Adult; D000367:Age Factors; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012680:Sensitivity and Specificity; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D015595:Skin Aging / Q000473:pathology* / Q000502:physiology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D003094:Collagen; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone