s100a4 Signaling in Fibrotic Diabetic Tendon Healing

肌腱损伤的有效手术修复是有限的，因为疤痕组织往往会介导愈合 而不是自然肌腱结构的再生。这种纤维性瘢痕组织会导致肌腱功能受损，原因是 相对于健康的肌腱，细胞外基质(ECM)组织紊乱，力学性能较差。类型 II型糖尿病(T2 DM)极大地加剧了这种治愈模式，导致更深刻的损失 影响肌腱功能，增加再断裂的发生率。我们对治理机制的理解 糖尿病肌腱纤维化愈合的增加仍然是有限的，这一知识差距导致了 缺乏改善临床结果的治疗靶点。我们之前的研究利用了一种小鼠模型 饮食引起的肥胖和导致瘢痕形成增加和机械性能下降的T2 DM 然而，在肌腱愈合过程中，驱动这些损伤的机制尚不清楚。我们的 初步数据表明，细胞外S100a4(S100钙结合蛋白4A)信号是 非糖尿病动物的纤维性肌腱愈合。S100a4-单倍体功能不全减少疤痕并加速 相对于WT，机械性能的改善，而S100a4细胞的耗尽也减少了疤痕组织 形成，但降低机械性能，这表明S100a4产生细胞是 机械充分的肌腱愈合。鉴于S100a4和愤怒的表达在 糖尿病肌腱修复我们认为糖尿病肌腱的纤维化愈合程度比 由于S100a4-RAGE信号升高而导致的非糖尿病。因此，在本研究中，我们将使用小鼠模型 饮食诱导肥胖和2型糖尿病合并急性肌腱损伤和修复的中枢假说检验 抑制糖尿病患者肝纤维化前S100a4-RAGE活性的增强和持续激活 肌腱将促进机械上优越的、再生的肌腱愈合。我们将通过以下方式检验这一假设 以下具体目标：目标1：确定肌腱愈合过程中产生S100a4的细胞群和 S100a4条件性缺失对瘢痕组织形成和机械强度获得的特异性影响 糖尿病肌腱损伤后。目标2：确定RAGE的全局和巨噬细胞特异性缺失的影响 关于瘢痕介导的糖尿病肌腱愈合作为S100a4信号减少的机制。目标3：评估 小分子抑制S100a4和RAGE促进糖尿病肌腱愈合的疗效。

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.