Determining the Role of TGF Beta Type II Receptor on Lysyl Oxidase Production
Abstract
Tendons transfer forces from muscle to bone and are vital to movement. Unfortunately, tendons are injured frequently and have poor self-healing capability. Current therapies are unable to restore damaged tendons to their prior strength. Tissue engineering using mesenchymal stem cells (MSCs) is being investigated in strategies to develop functional tendon replacements or repairs. A current challenge is the limited information on the regulators of MSC differentiation into specialized tendon cells (tenogenesis) and control of functional tendon formation. Prior work showed that the transforming growth factor beta (TGF-β) family of cytokines are critical in regulating tenogenesis and the production of lysyl oxidase (LOX), an enzyme that mediates collagen crosslinking and functional tendon formation. TGF-β may activate the TGF-β type-II receptor (TGF-βRII), a transmembrane protein that recruits and phosphorylates TGF-βRI when bound by a TGF-β ligand However, how TGF-βRII signaling controls the TGF-β response in MSCs to regulate LOX production is unclear. The objective of this study was to determine how inhibition of TGF-βRII impacts LOX levels in MSCs. We are exploring inhibiting TGF-βRII using both a chemical agent as well as siRNA and evaluating the impacts on MSCs and LOX levels. The outcomes of these studies will show how TGF-β signaling through TGF-βRII in MSCs regulates LOX levels, which can be used to direct functional tendon tissue formation and future regenerative therapies.
Determining the Role of TGF Beta Type II Receptor on Lysyl Oxidase Production
Tendons transfer forces from muscle to bone and are vital to movement. Unfortunately, tendons are injured frequently and have poor self-healing capability. Current therapies are unable to restore damaged tendons to their prior strength. Tissue engineering using mesenchymal stem cells (MSCs) is being investigated in strategies to develop functional tendon replacements or repairs. A current challenge is the limited information on the regulators of MSC differentiation into specialized tendon cells (tenogenesis) and control of functional tendon formation. Prior work showed that the transforming growth factor beta (TGF-β) family of cytokines are critical in regulating tenogenesis and the production of lysyl oxidase (LOX), an enzyme that mediates collagen crosslinking and functional tendon formation. TGF-β may activate the TGF-β type-II receptor (TGF-βRII), a transmembrane protein that recruits and phosphorylates TGF-βRI when bound by a TGF-β ligand However, how TGF-βRII signaling controls the TGF-β response in MSCs to regulate LOX production is unclear. The objective of this study was to determine how inhibition of TGF-βRII impacts LOX levels in MSCs. We are exploring inhibiting TGF-βRII using both a chemical agent as well as siRNA and evaluating the impacts on MSCs and LOX levels. The outcomes of these studies will show how TGF-β signaling through TGF-βRII in MSCs regulates LOX levels, which can be used to direct functional tendon tissue formation and future regenerative therapies.