Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing.
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.
Katzel
Evan B
EB
Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA.
Wolenski
Matthew
M
Loiselle
Alayna E
AE
Basile
Patrick
P
Flick
Lisa M
LM
Langstein
Howard N
HN
Hilton
Matthew J
MJ
Awad
Hani A
HA
Hammert
Warren C
WC
O'Keefe
Regis J
RJ
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*
D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse