Department of Orthopaedics, University of Maryland, Baltimore, Maryland, USA.
Department of Orthopaedic Surgery, Graduate School of Biomedical and Health sciences, Hiroshima University, Hiroshima, Japan.
J Orthop Res. 2022 Jun;40(6):1409-1419. doi: 10.1002/jor.25176. Epub 2021 Sep 8.
Injured tendons do not regain their native structure except at fetal or very young ages. Healing tendons often show mucoid degeneration involving accumulation of sulfated glycosaminoglycans (GAGs), but its etiology and molecular base have not been studied substantially. We hypothesized that quality and quantity of gene expression involving the synthesis of proteoglycans having sulfated GAGs are altered in injured tendons and that a reduction in synthesis of sulfated GAGs improves structural and functional recovery of injured tendons. C57BL6/j mice were subjected to Achilles tendon tenotomy surgery. The injured tendons accumulated sulfate proteoglycans as early as 1-week postsurgery and continued so by 4-week postsurgery. Transcriptome analysis revealed upregulation of a wide range of proteoglycan genes that have sulfated GAGs in the injured tendons 1 and 3 weeks postsurgery. Genes critical for enzymatic reaction of initiation and elongation of chondroitin sulfate GAG chains were also upregulated. After the surgery, mice were treated with the 2-deoxy-d-glucose (2DG) that inhibits conversion of glucose to glucose-6-phosphate, an initial step of glucose metabolism as an energy source and precursors of monosaccharides of GAGs. The 2DG treatment reduced accumulation of sulfated proteoglycans, improved collagen fiber alignment, and reduced the cross-sectional area of the injured tendons. The modulus of the 2DG-treated groups was higher than that in the vehicle group, but not of statistical significance. Our findings suggest that mucoid degeneration in injured tendons may result from the upregulated expression of genes involved the synthesis of sulfate proteoglycans and can be inhibited by reduction of glucose utilization.
受伤的肌腱除了在胎儿期或非常年幼时外，无法恢复其固有结构。愈合的肌腱常表现出黏液样变性，涉及硫酸化糖胺聚糖（GAG）的积累，但尚未对其病因和分子基础进行深入研究。我们假设，涉及具有硫酸化 GAG 的蛋白聚糖合成的基因表达的质量和数量在受伤的肌腱中发生改变，并且 GAG 合成的减少可以改善受伤肌腱的结构和功能恢复。C57BL6/j 小鼠接受跟腱切断术。受伤的肌腱早在手术后 1 周就开始积累硫酸软骨素蛋白聚糖，并在手术后 4 周持续积累。转录组分析显示，受伤肌腱中具有硫酸化 GAG 的广泛范围的蛋白聚糖基因在手术后 1 周和 3 周上调。参与硫酸软骨素 GAG 链起始和延伸的酶反应的关键基因也上调。手术后，用 2-脱氧-D-葡萄糖（2DG）处理小鼠，该药物抑制葡萄糖转化为葡萄糖-6-磷酸，葡萄糖-6-磷酸是葡萄糖代谢的初始步骤，也是 GAG 单糖前体的能量来源。2DG 治疗减少了硫酸软骨素蛋白聚糖的积累，改善了胶原纤维排列，并减少了受伤肌腱的横截面积。2DG 处理组的模量高于载体组，但无统计学意义。我们的研究结果表明，受伤肌腱中的黏液样变性可能是由于参与硫酸软骨素蛋白聚糖合成的基因表达上调所致，并且可以通过减少葡萄糖利用来抑制。
