Incomplete tendon healing leads to significant mobility restriction, pain and health care cost. While a large number of clinical and preclinical approaches for drug- and cell-based therapies, rehabilitation and physical therapy, and other treatment modalities have been attempted, none result in complete recovery of mechanical structure and function in injured tendons. To address this major clinical problem, it is necessary to define the molecular changes and mechanisms governing the tendon healing process in order to develop novel targeted therapies for tendon injury. Interestingly, up-regulation of glycolysis and lactate synthesis occurs in wound, inflammation, immune response and cancer, and is critical for growth/survival of cancerous tumors and polarizing of macrophages. Furthermore, substantial evidence demonstrates that these metabolic changes control growth and differentiation of stem and progenitor cells. These findings support our new concept that modifying metabolic changes would be an effective therapeutic approach for tissue repair and regeneration. Recently we determined that IL-1?, which is up-regulated at the tendon injury site, stimulated the expression of glycolytic enzymes and lactate production in injured-tendon derived progenitors. In addition, once the progenitors were exposed to IL-1?, they irreversibly reduced the ability to express tenogenic markers and increased the requirement of lactate synthesis for their proliferation. Our in vivo preliminary data showed that injured tendons acutely increased an influx of glucose to glyceraldehyde (a metabolite of glycolysis) and lactate. Furthermore, treatment with the pharmacological inhibitor of lactate synthesis, dichroloacetate (DCA), decreased the cross-sectional area of injured tendons, stimulated collagen fiber alignment, increased fiber diameters and dramatically improved the biomechanical properties of injured tendons. Therefore, we have developed the novel hypothesis that glycolysis and lactate synthesis are up-regulated in tendons after injury and correction of this alteration directly stimulates tendon healing. The overall objectives of this study are (1) to determine the metabolic changes during tendon healing and (2) to develop targeted metabolic drugs for tendon repair. To verify our central hypothesis, we propose three Specific Aims: (1) To establish spatiotemporal correlations between glucose metabolism in tendons after acute injury and tendon healing; (2) To examine the effects of glycolysis and lactate synthesis modifiers on tendon healing; and (3) To determine the mechanisms by which inhibition of lactate synthesis stimulates tendon repair while repressing scar formation. The outcome of the project will produce a novel link between glucose metabolism and tendon healing, leading to the development of metabolic modifiers with the ability to promote tendon repair. It will also reveal a novel mechanism of scar formation involving lactate metabolism.
Nearly 5 million patients visit a physician for tendon pain each year in the US and yet, current therapies for acute or chronic tendon damage and disorders remain ineffective. This project aims to test the efficacy of a new drug treatment for tendon repair and is of major translational research relevance for skeletal diseases.
