Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Biomedical Engineering, University of Texas, Austin, Texas, USA.
J Orthop Res. 2023 Feb;41(2):278-289. doi: 10.1002/jor.25354. Epub 2022 May 13.
Enriched in glycolytic enzymes, paucicellular and hypovascular intrasynovial flexor tendons fail to mount an effective healing response after injury and repair. In contrast, well-vascularized extrasynovial flexor tendons possess high levels of oxidative phosphorylation (OXPHOS) enzymes and have a markedly improved healing capacity. This study was designed to compare the metabolic profiles of the two types of tendons and to evaluate the impact of metabolic reprogramming on early intrasynovial tendon healing in a clinically relevant canine model. Results showed that healthy intrasynovial tendons expressed higher levels of PDK1 and GAPDH and lower levels of SCX and IGF1 than did extrasynovial tendons. PDK1 encodes a subtype of pyruvate dehydrogenase kinase (PDK) that inhibits OXPHOS. Consistently, ATP production via glycolysis was favored in intrasynovial tendon cells whereas OXPHOS was the preferred pathway in extrasynovial tendon cells. Inhibition of glycolysis in vitro increased SCX expression in intrasynovial tendon cells. Therefore, dichloroacetate (DCA), a PDK1 inhibitor, was used in vivo to shift intrasynovial tendon ATP production from glycolysis to OXPHOS. Oral DCA administration reduced serum lactate concentration and increased acetyl-CoA content in repaired intrasynovial tendons and led to reduced TLR4 and IL1B and increased IGF1, SCX, and TGFB3 expressions in treated intrasynovial tendons compared to controls. Immunohistochemistry staining with anti-Ki67 and anti-CD31 antibodies revealed marked increases in cellularity and neovascularization in treated intrasynovial tendons. Clinical significance: The findings of this experiment indicate that improved gene expression and histological outcomes can be achieved by regulating glucose metabolism in the early stages following intrasynovial tendon repair.
富含糖酵解酶的少细胞和低血管性滑膜内屈肌腱在受伤和修复后无法产生有效的愈合反应。相比之下，富含血管的滑膜外屈肌腱具有高水平的氧化磷酸化（OXPHOS）酶，并且具有明显改善的愈合能力。本研究旨在比较两种类型的肌腱的代谢谱，并评估代谢重编程对临床相关犬模型中早期滑膜内肌腱愈合的影响。结果表明，健康的滑膜内肌腱表达的 PDK1 和 GAPDH 水平较高，而 SCX 和 IGF1 水平较低。PDK1 编码一种丙酮酸脱氢酶激酶（PDK）亚型，可抑制 OXPHOS。一致地，滑膜内肌腱细胞中通过糖酵解产生的 ATP 产生受到青睐，而 OXPHOS 是滑膜外肌腱细胞中的首选途径。体外抑制糖酵解可增加滑膜内肌腱细胞中 SCX 的表达。因此，在体内使用 PDK1 抑制剂二氯乙酸（DCA）将滑膜内肌腱的 ATP 产生从糖酵解转移到 OXPHOS。口服 DCA 给药可降低修复后滑膜内肌腱中的血清乳酸浓度并增加乙酰辅酶 A 含量，并导致治疗后的滑膜内肌腱中的 TLR4 和 IL1B 减少，IGF1、SCX 和 TGFB3 表达增加与对照组相比。用抗 Ki67 和抗 CD31 抗体进行免疫组织化学染色显示，治疗后的滑膜内肌腱中细胞数量和新生血管化明显增加。临床意义：该实验的结果表明，通过调节滑膜内肌腱修复后早期的葡萄糖代谢，可以实现改善的基因表达和组织学结果。
