title: Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing.
abstract: Studies were performed evaluating the role of Smad3, a transcription factor mediating canonical TGF-β signaling, on scarring and adhesion formation using an established flexor digitorum longus (FDL) tendon repair model. In unoperated animals the metatarsophalangeal (MTP) range of motion (ROM) was similar in Smad3(-/-) and wild-type (WT) mice while the basal tensile strength of Smad3(-/-) tendons was significantly (39%) lower than in WT controls. At 14 and 21 days following repair Smad3(-/-) MTP ROM reached approximately 50% of the basal level and was twice that observed in WT tendon repairs, consistent with reduced adhesion formation. Smad3(-/-) and WT maximal tensile repair strength on post-operative day 14 was similar. However, Smad3(-/-) tendon repairs maximal tensile strength on day 21 was 42% lower than observed in matched WT mice, mimicking the relative decrease in strength observed in Smad3(-/-) FDL tendons under basal conditions. Histology showed reduced "healing callus" in Smad3(-/-) tendons while quantitative PCR, in situ hybridization, and immunohistochemistry showed decreased col3a1 and col1a1 and increased MMP9 gene and protein expression in repaired Smad3(-/-) tendons. Thus, Smad3(-/-) mice have reduced collagen and increased MMP9 gene and protein expression and decreased scarring following tendon FDL tendon repair.
authors.affiliation: Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
authors.forename: Evan B
authors.initials: EB
authors.lastname: Katzel
authors.forename: Matthew
authors.initials: M
authors.lastname: Wolenski
authors.forename: Alayna E
authors.initials: AE
authors.lastname: Loiselle
authors.forename: Patrick
authors.initials: P
authors.lastname: Basile
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Flick
authors.forename: Howard N
authors.initials: HN
authors.lastname: Langstein
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hilton
authors.forename: Hani A
authors.initials: HA
authors.lastname: Awad
authors.forename: Warren C
authors.initials: WC
authors.lastname: Hammert
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000209:etiology / Q000503:physiopathology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D008682:Metatarsal Bones; D051379:Mice; D016059:Range of Motion, Articular / Q000502:physiology; D051900:Smad3 Protein / Q000172:deficiency*; D013708:Tendon Injuries / Q000503:physiopathology*; D013710:Tendons / Q000502:physiology*; D013718:Tensile Strength / Q000502:physiology; D000267:Tissue Adhesions / Q000209:etiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse