Tendon Development and Injury Repair
Tendons are critical structures that attach muscle to bone. Their ability to glide within surrounding tissues is essential for skeletal motion. Following injury, however, scar formation is common and prevents their ability to glide. We have successfully developed a Flexor Digitorum Longus (FDL) segmental tendon injury and replacement model in the mouse that permits us to examine the tendon healing process and design novel approaches to inhibit tendon scarring. Using this model, we have been able to define some factors that might be responsible for the scarring that occurs following tendon reconstruction. One such factor is Transforming Growth Factor beta 1 (TGF-β). Canonical TGF-β signaling results in phosphorylation of receptor associated Smads, Smad2 and Smad3. Following their activation, Smad2 or Smad3 form a complex in the cytoplasm with the co-Smad, Smad4. The complex is subsequently transported to the nucleus where it binds DNA to regulate gene transcription. We have demonstrated that Smad3-/- mice have reduced adhesions following tendon injury compared to wild type mice. We are currently testing whether treatment of FDL tendon injured mice with anti-sense oligonucleotides targeting components of the TGF-β signaling pathway can reduce scar formation. Additionally, we are examining the role of non-canonical, or Smad-independent, TGF-β/Tak1β signaling in the tendon healing process. Finally, we are initiating studies aimed at defining the role of TGF-β/Tak1 and a several other signaling pathways in tendon development.