title: Remodeling of murine intrasynovial tendon adhesions following injury: MMP and neotendon gene expression.
abstract: Tendon injury frequently results in the formation of adhesions that reduce joint range of motion. To study the cellular, molecular, and biomechanical events involved in intrasynovial tendon healing and adhesion formation, we developed a murine flexor tendon healing model in which the flexor digitorum longus (FDL) tendon of C57BL/6 mice was transected and repaired using suture. This model was used to test the hypothesis that murine flexor tendons heal with differential expression of matrix metalloproteases (MMPs), resulting in the formation of scar tissue as well as the subsequent remodeling of scar and adhesions. Healing tendons were evaluated by histology, gene expression via real-time RT-PCR, and in situ hybridization, as well as biomechanical testing to assess the metatarsophalangeal (MTP) joint flexion range of motion (ROM) and the tensile failure properties. Tendons healed with a highly disorganized fibroblastic tissue response that was progressively remodeled through day 35 resulting in a more organized pattern of collagen fibers. Initial repair involved elevated levels of Mmp-9 at day 7, which is associated with catabolism of damaged collagen fibers. High levels of Col3 are consistent with scar tissue, and gradually transition to the expression of Col1. Scleraxis expression peaked at day 7, but the expression was limited to the original tendon adjacent to the injury site, and no expression was present in granulation tissue involved in the repair response. The MTP joint ROM with standardized force on the tendon was decreased on days 14 and 21 compared to day 0, indicating the presence of adhesions. Peak expressions of Mmp-2 and Mmp-14 were observed at day 21, associated with tendon remodeling. At day 28, two genes associated with neotendon formation, Smad8 and Gdf-5, were elevated and an improvement in MTP ROM occurred. Tensile strength of the tendon progressively increased, but by 63 days the repaired tendons had not reached the tensile strength of normal tendon. The murine model of primary tendon repair, described here, provides a novel mechanism to study the tendon healing process, and further enhances the understanding of this process at the molecular, cellular, and biomechanical level.
authors.affiliation: Department of Orthopaedics, The Center for Musculoskeletal Research, University of Rochester-Box 665, 601 Elmwood Avenue, Rochester, New York 14620, USA.
authors.forename: Alayna E
authors.initials: AE
authors.lastname: Loiselle
authors.forename: Gwynne A
authors.initials: GA
authors.lastname: Bragdon
authors.forename: Justin A
authors.initials: JA
authors.lastname: Jacobson
authors.forename: Sys
authors.initials: S
authors.lastname: Hasslund
authors.forename: Zenia E
authors.initials: ZE
authors.lastname: Cortes
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: David J
authors.initials: DJ
authors.lastname: Mitten
authors.forename: Hani A
authors.initials: HA
authors.lastname: Awad
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001696:Biomechanical Phenomena; D002921:Cicatrix / Q000473:pathology / Q000503:physiopathology; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000502:physiology; D053511:Matrix Metalloproteinase 14 / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D013583:Synovial Membrane / Q000166:cytology / Q000293:injuries* / Q000502:physiology*; D013708:Tendon Injuries / Q000473:pathology / Q000503:physiopathology*; D000267:Tissue Adhesions / Q000473:pathology / Q000503:physiopathology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D024042:Collagen Type I; D024061:Collagen Type III; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases; C503815:Scx protein, mouse