Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Shriners Hospitals for Children-Saint Louis, St. Louis, Missouri, USA.
FASEB J. 2024 Jul 15;38(13):e23778. doi: 10.1096/fj.202400883R.
The mechanosensitive ion channels Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 transduce physiologic and supraphysiologic magnitudes of mechanical signals in the chondrocyte, respectively. TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remain to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes and also exhibit unique co-regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)-1-responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. These findings emphasize the presence of a broad "mechanome" with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.
机械敏感性离子通道瞬时受体电位香草酸 4（TRPV4）和 PIEZO1 分别转导软骨细胞的生理和超生理机械信号。TRPV4 的激活促进软骨生成，而超生理变形激活 PIEZO1 则导致细胞死亡。这些通道的激活如何离散地驱动基因表达的变化从而改变细胞行为的机制仍有待确定。迄今为止，尚无研究对比这些通道激活后的转录组反应，也没有任何已发表的数据试图将这些转录组与细胞功能的改变相关联。本研究使用 RNA 测序全面研究了与 TRPV4 或 PIEZO1 激活相关的转录组，结果表明 TRPV4 和 PIEZO1 驱动不同的转录组，并且还表现出独特的共调节基因簇。值得注意的是，通过超生理变形激活 PIEZO1 诱导了短暂的炎症表型，与白细胞介素 (IL)-1 反应转录组重叠，并包含与软骨降解和骨关节炎进展相关的基因。然而，TRPV4 和 PIEZO1 也被证明具有合成代谢作用。PIEZO1 在未加载条件下表达促进了促软骨生成的转录组，并且每天用 PIEZO1 激动剂 Yoda1 处理可显著增加体外硫酸化糖胺聚糖的沉积。这些发现强调了存在广泛的“机械组”，其中 TRPV4 和 PIEZO1 的激活具有不同的作用，提示 PIEZO1 在软骨细胞的生理和病理反应中具有复杂的作用。鉴定 PIEZO1 特有的或与 TRPV4 共享的转录组谱（与 IL-1 诱导的炎症不同）可为针对这些通道的治疗设计提供信息，以用于骨关节炎的管理和治疗。
