Cellular and molecular mechanism underlying alcohol inhibition of bone fracture healing

7.项目摘要/摘要 F31的应用是为了研究酒精抑制骨骼的细胞和分子机制 骨折愈合。饮酒会增加冒险行为，并会导致骨骼受伤 骨折。此外，使用酒精的患者骨折不愈合的风险增加，这与 增加的医疗成本和大量的患者发病率。骨折修复是一个复杂的过程，涉及 损伤部位局部骨膜间充质干细胞向软骨细胞分化的实验研究 成骨细胞形成骨折骨痂。我们实验室此前曾报道，啮齿动物暴露在发作性疾病中 酒精在胫骨中线骨折前形成有缺陷的骨折骨痂，其特征是 软骨骨痂的体积、直径和软骨成熟受阻的组织学证据。这些数据 提示酒精可能通过抑制MSC向软骨的分化而抑制骨折骨痂的形成。 骨科血统。众所周知，酒精暴露会产生细胞内活性氧物种(ROS)，以及ROS 已被证明在调节MSC自我更新和分化的细胞信号中发挥重要作用。 然而，ROS与软骨-骨分化抑制之间的分子机制尚不清楚。 描述。叉头盒O(FoxO)转录分子氧化应激反应家族的激活 已有研究表明，这些因素对整体骨骼健康有害，此前有报道称，FoxO- 已有研究表明，特定的信号通路可以拮抗对MSC软骨-骨至关重要的典型的Wnt信号活性 世系承诺。最近，我们报道了FoxO1/3的激活与愈伤组织的减少有关 酒精暴露的啮齿动物骨折损伤后的面积。基于这些初步发现，我们假设 酒精暴露通过抑制MSC在骨折骨痂内的软骨向骨分化 ROS介导的增强FoxO1/3信号转导。为了验证这一假设，我们提出了以下目标。目标1 将表征酒精骨折骨痂内MSC软骨细胞系分化的变化- 裸露的啮齿动物。目的2将确定酒精对原代间充质干细胞分化的影响以及 MSC FoxO1/3信号的减弱恢复了MSC的分化。总体而言，我们预计这项研究将开启新的 减少饮酒和骨骼相关风险的治疗干预途径 骨折修复。

7. Project Summary/Abstract This F31 application is to investigate the cellular and molecular mechanisms underlying alcohol inhibition of bone fracture healing. Alcohol consumption is associated with increased risk-taking and injuries leading to a bone fracture. In addition, patients using alcohol have an increased risk of fracture nonunion, which is associated with increased healthcare costs and substantial patient morbidity. Bone fracture repair is a complex process involving the differentiation of local periosteum mesenchymal stem cells (MSC) near the injury site into chondrocytes and osteoblasts to form a fracture callus. Our laboratory has previously reported that rodents exposed to episodic alcohol preceding a midline tibia fracture develop a deficient fracture callus as characterized by a reduced cartilaginous callus volume, diameter and histological evidence of inhibited cartilage maturation. These data suggest that alcohol may be inhibiting fracture callus formation by inhibiting the differentiation of MSC to chondro- osteo lineages. Alcohol exposure is known to produce intracellular reactive oxygen species (ROS), and ROS has been shown to play an important role in cellular signaling regulating MSC self-renewal and differentiation. However, the molecular mechanism connecting ROS to chondro-osteo differentiation inhibition has yet to be described. Activation of molecular oxidative stress responder family of forkhead box O (FoxO) transcription factors have been shown to be detrimental to overall bone health, and it has been previously reported that FoxO- specific signaling has been shown to antagonize Canonical Wnt signaling activity critical for MSC chondro-osteo lineage commitment. Recently, we have reported that FoxO1/3 activation is associated with decreased callus area following fracture injury in alcohol-exposed rodents. Based on these preliminary findings, we hypothesize that alcohol-exposure inhibits MSC to chondro-osteo differentiation within the fracture callus through ROS-mediated enhanced FoxO1/3 signaling. To test this hypothesis, we propose the following aims. Aim 1 will characterize alterations in MSC chondrogenic lineage differentiation within the fracture callus of alcohol- exposed rodents. Aim 2 will determine the effect of alcohol on primary MSC differentiation and whether attenuation of MSC FoxO1/3 signaling restores MSC differentiation. Overall, we expect this study will open new avenues for therapeutic intervention to attenuate the risks associated with alcohol consumption and bone fracture repair.