title: Development of antisense oligonucleotide (ASO) technology against Tgf-β signaling to prevent scarring during flexor tendon repair.
abstract: Flexor tendons (FT) in the hand provide near frictionless gliding to facilitate hand function. Upon injury and surgical repair, satisfactory healing is hampered by fibrous adhesions between the tendon and synovial sheath. In the present study we used antisense oligonucleotides (ASOs), specifically targeted to components of Tgf-β signaling, including Tgf-β1, Smad3 and Ctgf, to test the hypothesis that local delivery of ASOs and suppression of Tgf-β1 signaling would enhance murine FT healing by suppressing adhesion formation while maintaining strength. ASOs were injected in to the FT repair site at 2, 6 and 12 days post-surgery. ASO treatment suppressed target gene expression through 21 days. Treatment with Tgf-β1, Smad3 or Ctgf ASOs resulted in significant improvement in tendon gliding function at 14 and 21 days, relative to control. Consistent with a decrease in adhesions, Col3a1 expression was significantly decreased in Tgf-β1, Smad3 and Ctgf ASO treated tendons relative to control. Smad3 ASO treatment enhanced the maximum load at failure of healing tendons at 14 days, relative to control. Taken together, these data support the use of ASO treatment to improve FT repair, and suggest that modulation of the Tgf-β1 signaling pathway can reduce adhesions while maintaining the strength of the repair.
authors.affiliation: Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester Medical Center, Rochester, New York.
authors.forename: Alayna E
authors.initials: AE
authors.lastname: Loiselle
authors.forename: Kiminori
authors.initials: K
authors.lastname: Yukata
authors.forename: Michael B
authors.initials: MB
authors.lastname: Geary
authors.forename: Sirish
authors.initials: S
authors.lastname: Kondabolu
authors.forename: Shanshan
authors.initials: S
authors.lastname: Shi
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Jonason
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; D002921:Cicatrix / Q000517:prevention & control; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051900:Smad3 Protein / Q000037:antagonists & inhibitors*; D013708:Tendon Injuries / Q000628:therapy*; D013710:Tendons / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D016376:Oligonucleotides, Antisense; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Antisense oligonucleotides; Ctgf; Flexor tendon healing; Smad3; Tgf-β1