title: Adamts5 deletion blocks murine dermal repair through CD44-mediated aggrecan accumulation and modulation of transforming growth factor β1 (TGFβ1) signaling.
abstract: ADAMTS5 has been implicated in the degradation of cartilage aggrecan in human osteoarthritis. Here, we describe a novel role for the enzyme in the regulation of TGFβ1 signaling in dermal fibroblasts both in vivo and in vitro. Adamts5(-/-) mice, generated by deletion of exon 2, exhibit impaired contraction and dermal collagen deposition in an excisional wound healing model. This was accompanied by accumulation in the dermal layer of cell aggregates and fibroblastic cells surrounded by a pericellular matrix enriched in full-length aggrecan. Adamts5(-/-) wounds exhibit low expression (relative to wild type) of collagen type I and type III but show a persistently elevated expression of tgfbRII and alk1. Aggrecan deposition and impaired dermal repair in Adamts5(-/-) mice are both dependent on CD44, and Cd44(-/-)/Adamts5(-/-) mice display robust activation of TGFβ receptor II and collagen type III expression and the dermal regeneration seen in WT mice. TGFβ1 treatment of newborn fibroblasts from wild type mice results in Smad2/3 phosphorylation, whereas cells from Adamts5(-/-) mice phosphorylate Smad1/5/8. The altered TGFβ1 response in the Adamts5(-/-) cells is dependent on the presence of aggrecan and expression of CD44, because Cd44(-/-)/Adamts5(-/-) cells respond like WT cells. We propose that ADAMTS5 deficiency in fibrous tissues results in a poor repair response due to the accumulation of aggrecan in the pericellular matrix of fibroblast progenitor cells, which prevents their transition to mature fibroblasts. Thus, the capacity of ADAMTS5 to modulate critical tissue repair signaling events suggests a unique role for this enzyme, which sets it apart from other members of the ADAMTS family of proteases.
authors.affiliation: Departments of Biochemistry, Rush UniversityMedical Center, Chicago, Illinois 60612, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Velasco
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Luisa
authors.initials: L
authors.lastname: DiPietro
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Stepp
authors.forename: John D
authors.initials: JD
authors.lastname: Sandy
authors.forename: Anna
authors.initials: A
authors.lastname: Plaas
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency* / Q000235:genetics; D000071116:ADAMTS5 Protein; D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D030301:Activin Receptors, Type II; D053674:Aggrecans / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002449:Cell Aggregation / Q000187:drug effects; D020405:Dermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015622:Epithelioid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics*
chemical_list: D053674:Aggrecans; D018960:Hyaluronan Receptors; D018125:Receptors, Transforming Growth Factor beta; D051896:Smad Proteins, Receptor-Regulated; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D000077293:Receptor, Transforming Growth Factor-beta Type I; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse