Tsuchiya Yuta, Matsuo Hikaru, Asahara Hiroshi, Inui Masafumi
Laboratory of Animal Regeneration Systemology, Department of Life Sciences, School of Agriculture, Meiji University, Kanagawa, 214-8571, Japan.
Department of Systems BioMedicine, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Biochem Biophys Rep. 2025 Jul 23;43:102178. doi: 10.1016/j.bbrep.2025.102178. eCollection 2025 Sep.
Tendon is the fibrous tissue that connects skeletal muscle and bone, playing a crucial role in transmitting forces generated in muscles to bones and thereby facilitating locomotion. Tendon is continuously subjected to mechanical stimuli, such as tensile force and shear stress, and it is well documented that tendon cells respond to these forces and modulate gene expression and tissue structures. However, whether or how tenocytes respond to matrix stiffness, another key mechanical cue for the tissue, remained elusive. While previous studies have shown that mesenchymal stem cells (MSCs) or tendon derived stem cells (TDSCs) modulate tenogenic gene expression in response to stiffness, its effect on tendon fibroblasts was unclear. In this study, we investigated the role of matrix stiffness on tenocytes derived from tail and Achilles tendon of young rats. Tenocytes displayed stiffness-dependent difference in expression of key tendon-related genes, including Mkx, particularly at 40 kPa stiffness. Interestingly, the transient receptor potential melastatin 7 (TRPM7) channel was identified as an upstream regulator of stiffness-dependent Mkx expression. TRPM7 expression was elevated at 40 kPa stiffness, and its knockdown reduced Mkx expression while abolishing the stiffness-dependent expression pattern. This regulation likely occurs through intracellular calcium (Ca) and/or magnesium (Mg) ion influx, as Mkx expression was promoted upon Ca ionophore treatment or elevation of extracellular Mg concentration. This study underscores the importance of stiffness in tendon biology and adds a novel layer to the transcriptional regulation of Mkx, with implications for understanding tendon development, maintenance, and mechanotransduction.
肌腱是连接骨骼肌和骨骼的纤维组织，在将肌肉产生的力量传递到骨骼从而促进运动方面发挥着关键作用。肌腱不断受到机械刺激，如拉力和剪切应力，并且有充分的文献记载肌腱细胞会对这些力量做出反应并调节基因表达和组织结构。然而，肌腱细胞是否以及如何对基质硬度（该组织的另一个关键机械信号）做出反应仍然不清楚。虽然先前的研究表明间充质干细胞（MSCs）或肌腱衍生干细胞（TDSCs）会响应硬度调节肌腱生成基因的表达，但其对肌腱成纤维细胞的影响尚不清楚。在本研究中，我们研究了基质硬度对年轻大鼠尾巴和跟腱来源的肌腱细胞的作用。肌腱细胞在关键肌腱相关基因（包括Mkx）的表达上表现出硬度依赖性差异，特别是在40 kPa硬度下。有趣的是，瞬时受体电位香草酸亚型7（TRPM7）通道被确定为硬度依赖性Mkx表达的上游调节因子。TRPM7表达在40 kPa硬度下升高，其敲低会降低Mkx表达，同时消除硬度依赖性表达模式。这种调节可能通过细胞内钙（Ca）和/或镁（Mg）离子内流发生，因为在钙离子载体处理或细胞外镁浓度升高时Mkx表达会被促进。本研究强调了硬度在肌腱生物学中的重要性，并为Mkx的转录调节增加了新的层面，对理解肌腱发育、维持和机械转导具有重要意义。
