title: TGF-β1 Suppresses Plasmin and MMP Activity in Flexor Tendon Cells via PAI-1: Implications for Scarless Flexor Tendon Repair.
abstract: Flexor tendon injuries caused by deep lacerations to the hands are a challenging problem as they often result in debilitating adhesions that prevent the movement of the afflicted fingers. Evidence exists that tendon adhesions as well as scarring throughout the body are largely precipitated by the pleiotropic growth factor, Transforming Growth Factor Beta 1(TGF-β1), but the effects of TGF-β1 are poorly understood in tendon healing. Using an in vitro model of tendon healing, we previously found that TGF-β1 causes gene expression changes in tenocytes that are consistent with scar tissue and adhesion formation, including upregulation of the anti-fibrinolytic protein, PAI-1. Therefore, we hypothesized that TGF-β1 contributes to scarring and adhesions by reducing the activity of proteases responsible for ECM degradation and remodeling, such as plasmin and MMPs, via upregulation of PAI-1. To test our hypothesis, we examined the effects of TGF-β1 on the protease activity of tendon cells. We found that flexor tendon tenocytes treated with TGF-β1 had significantly reduced levels of active MMP-2 and plasmin. Interestingly, the effects of TGF-β1 on protease activity were completely abolished in tendon cells from homozygous plasminogen activator inhibitor 1 (PAI-1) knockout (KO) mice, which are unable to express PAI-1. Our findings support the hypothesis that TGF-β1 induces PAI-1, which suppresses plasmin and plasmin-mediated MMP activity, and provide evidence that PAI-1 may be a novel therapeutic target for preventing adhesions and promoting a scarless, regenerative repair of flexor tendon injuries.
authors: Department of Biomedical Engineering, 601 Elmwood Ave, Rochester, New York.|The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.
authors: Youssef M
authors: YM
authors: Farhat
authors: The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.
authors: Alaa A
authors: AA
authors: Al-Maliki
authors: The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.
authors: Anas
authors: A
authors: Easa
authors: The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.|Department of Orthopaedics University of Rochester, 601 Elmwood Ave, Rochester, New York.
authors: Regis J
authors: RJ
authors: O'Keefe
authors: The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.|Department of Orthopaedics University of Rochester, 601 Elmwood Ave, Rochester, New York.
authors: Edward M
authors: EM
authors: Schwarz
authors: Department of Biomedical Engineering, 601 Elmwood Ave, Rochester, New York.|The Center for Musculoskeletal Research, 601 Elmwood Ave, Rochester, New York.|Department of Orthopaedics University of Rochester, 601 Elmwood Ave, Rochester, New York.
authors: Hani A
authors: HA
authors: Awad
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005341:Fibrinolysin / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D058258:Serpin E2 / Q000378:metabolism*; D013710:Tendons / Q000166:cytology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D053773:Transforming Growth Factor beta1; D005341:Fibrinolysin; D020782:Matrix Metalloproteinases