Effective surgical repair of tendon injuries is limited due to a propensity for scar tissue mediated healing rather than regeneration of native tendon structure. This fibrotic scar tissue results in impaired tendon function due to extracellular matrix (ECM) disorganization and inferior mechanical properties, relative to healthy tendon. Type II Diabetes Mellitus (T2DM) dramatically exacerbates this healing paradigm resulting in a more profound loss of tendon function, and increased incidence of re-rupture. Our understanding of the mechanisms that govern increased fibrotic healing in diabetic tendon remains limited, and this gap in knowledge has resulted in a paucity of therapeutic targets to improve clinical outcomes. Our previous studies have utilized a murine model of diet-induced obesity and T2DM that results in increased scar-formation and inferior mechanical properties during tendon healing, however, the mechanisms driving these impairments in healing are unknown. Our preliminary data identify extracellular S100a4 (S100 calcium binding protein 4A) signaling as a key driver of fibrotic tendon healing in non-diabetic animals. S100a4-haploinsufficiency decreases scarring and accelerates improvements in mechanical properties, relative to WT, while S100a4-cell depletion also decreases scar tissue formation, but decreases mechanical properties, suggesting that S100a4-producing cells are required for mechanically sufficient tendon healing. Given that S100a4 and RAGE expression are dramatically increased in diabetic tendon repairs we propose that fibrotic healing occurs to a greater degree in diabetic tendons than non-diabetic due to elevated S100a4-RAGE signaling. Thus, in the present study we will use a murine model diet induced obesity and T2DM in conjunction with acute tendon injury and repair to test the central hypothesis that inhibition of the increased and sustained activation of pro-fibrotic S100a4-RAGE activity in diabetic tendons will promote mechanically superior, regenerative tendon healing. We will test this hypothesis through the following specific aims: Aim 1: Identify the S100a4-producing cell population during tendon healing and the specific effects of S100a4 conditional deletion on scar tissue formation and acquisition of mechanical strength after injury in diabetic tendons. Aim 2: Define the effects of global and macrophage-specific deletion of RAGE on scar-mediated diabetic tendon healing as a mechanism of reduced S100a4 signaling. Aim 3: Assess the efficacy of small molecule inhibition of S100a4 and RAGE to improve diabetic tendon healing.

Following injury, tendons from individuals with Type II Diabetes Mellitus heal with an exuberant scar tissue response, resulting in tendons that are more prone to re-rupture or failure than non-diabetics, however the mechanism of impaired healing is unknown. We have identified the requirement for S100a4 signaling in scar-mediated tendon healing, and observe increased RAGE expression in diabetic tendon repairs. Thus, we will investigate the role of overactive S100a4-RAGE signaling as the predominant mechanism of impaired tendon healing in Type II Diabetics.