title: Intrinsic fibroblast-mediated remodeling of damaged collagenous matrices in vivo.
abstract: Numerous studies have examined wound healing and tissue repair after a complete tissue rupture and reported provisional matrix and scar tissue formation in the injury gap. The initial phases of the repair are largely mediated by the coagulation response and a principally extrinsic inflammatory response followed by type III collagen deposition to form scar tissue that may be later remodeled. In this study, we examine subfailure (Grade II sprain) damage to collagenous matrices in which no gross tissue gap is present and a localized concentration of provisional matrix or scar tissue does not form. This results in extracellular matrix remodeling that relies heavily upon type I collagen, and associated proteoglycans, and less heavily on type III scar tissue collagen. For instance, following subfailure tissue damage, collagen I and III expression was suppressed after 1 day, but by day 7 expression of both genes was significantly increased over controls, with collagen I expression significantly larger than type III expression. Concurrent with increased collagen expression were significantly increased expression of the collagen fibrillogenesis supporting proteoglycans fibromodulin, lumican, decorin, the large aggregating proteoglycan versican, and proteases cathepsin K and L. Interestingly, this remodeling process appears intrinsic with little or no inflammation response as damaged tissues show no changes in macrophage or neutrophils levels following injury and expression of the inflammatory markers, tumor necrosis factor-alpha and tartrate-resistant acid phosphatase were unchanged. Hence, since inflammation plays a large role in wound healing by inducing cell migration and proliferation, and controlling extracellular matrix scar formation, its absence leaves fibroblasts to principally direct tissue remodeling. Therefore, following a Grade II subfailure injury to the collagen matrix, we conclude that tissue remodeling is fibroblast-mediated and occurs without scar tissue formation, but instead with type I collagen fibrillogenesis to repair the tissue. As such, this system provides unique insight into acute tissue damage and offers a potentially powerful model to examine fibroblast behavior.
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA. ppproven@wisc.edu
authors.forename: Paolo P
authors.initials: PP
authors.lastname: Provenzano
authors.forename: Adriana L
authors.initials: AL
authors.lastname: Alejandro-Osorio
authors.forename: Wilmot B
authors.initials: WB
authors.lastname: Valhmu
authors.forename: Kristina T
authors.initials: KT
authors.lastname: Jensen
authors.forename: Ray
authors.initials: R
authors.lastname: Vanderby
mesh_terms: D000818:Animals; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000096:biosynthesis; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis; D002921:Cicatrix / Q000378:metabolism; D003094:Collagen / Q000737:chemistry*; D024061:Collagen Type III / Q000737:chemistry; D003238:Connective Tissue / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D017931:DNA Primers / Q000737:chemistry; D058575:Decorin; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism*; D000071235:Fibromodulin; D007150:Immunohistochemistry; D007249:Inflammation; D007632:Keratan Sulfate / Q000096:biosynthesis; D037181:Lectins, C-Type; D000071234:Lumican; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008855:Microscopy, Electron, Scanning; D015233:Models, Statistical; D010447:Peptide Hydrolases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D013997:Time Factors; D053675:Versicans; D014945:Wound Healing
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D024061:Collagen Type III; D017931:DNA Primers; C546880:Dcn protein, rat; D058575:Decorin; D016326:Extracellular Matrix Proteins; C000604334:Fmod protein, rat; D037181:Lectins, C-Type; C000604308:Lum protein, rat; D000071234:Lumican; D011509:Proteoglycans; D012333:RNA, Messenger; C508324:Vcan protein, rat; D000071235:Fibromodulin; D053675:Versicans; D012313:RNA; D003094:Collagen; D007632:Keratan Sulfate; D002403:Cathepsins; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534280:Ctsl protein, rat; D056657:Cathepsin K; C534133:Ctsk protein, rat