Stress deprivation of tendon explants or Tpm3.1 inhibition in tendon cells reduces F-actin to promote a tendinosis-like phenotype.
Stress deprivation of tendon explants or Tpm3.1 inhibition in tendon cells reduces F-actin to promote a tendinosis-like phenotype.
复制标题
DOI：
10.1091/mbc.e22-02-0067
复制
发表时间：
2022-12-01
影响因子：
3.3
通讯作者：
Parreno, Justin
中科院分区：
文献类型：
--
作者：
Inguito, Kameron L.;Schofield, Mandy M.;Faghri, Arya D.;Bloom, Ellen T.;Heino, Marissa;West, Valerie C.;Ebron, Karl Matthew M.;Elliott, Dawn M.;Parreno, Justin
肌动蛋白是机械力和细胞表型之间的中心介质。在肌腱中，据推测，机械应力剥夺通过减少丝状（F）-肌动蛋白来调节基因表达。然而，调节腱细胞F-肌动蛋白的机制仍不清楚。原肌球蛋白（Tpms）是F-肌动蛋白的主要调节因子。有超过40种Tpm同种型，每种都具有稳定F-肌动蛋白亚群的独特能力。我们研究了应力剥夺肌腱中的F-肌动蛋白聚合，并验证了应力纤维相关的Tpm（s）稳定F-肌动蛋白以调节细胞表型的假设。应激剥夺小鼠尾腱下调tenogenic和上调蛋白酶（基质金属蛋白酶-3）mRNA水平。伴随着mRNA的调制增加G/F-肌动蛋白，确认减少F-肌动蛋白的肌腱应力剥夺。为了研究F-肌动蛋白的分子调控，我们确定了尾部，跟腱和跖肌腱表达三种常见的亚型：Tpm 1.6，3.1和4.2。Tpm3.1与天然和原代肌腱细胞中的F-肌动蛋白相关。Tpm3.1抑制减少F-肌动蛋白，导致肌腱形成表达减少，软骨形成表达增加，以及小鼠和人肌腱细胞中蛋白酶表达增强。Tpm3.1抑制引起的这些表达变化与肌腱病进展一致。对骨骼肌细胞中F-肌动蛋白调控的进一步了解可能会导致新的治疗干预措施，以防止疾病进展过程中细胞表型的改变。
Actin is a central mediator between mechanical force and cellular phenotype. In tendons, it is speculated that mechanical stress deprivation regulates gene expression by reducing filamentous (F)-actin. However, the mechanisms regulating tenocyte F-actin remain unclear. Tropomyosins (Tpms) are master regulators of F-actin. There are more than 40 Tpm isoforms, each having the unique capability to stabilize F-actin subpopulations. We investigated F-actin polymerization in stress-deprived tendons and tested the hypothesis that stress fiber–associated Tpm(s) stabilize F-actin to regulate cellular phenotype. Stress deprivation of mouse tail tendon down-regulated tenogenic and up-regulated protease (matrix metalloproteinase-3) mRNA levels. Concomitant with mRNA modulation were increases in G/F-actin, confirming reduced F-actin by tendon stress deprivation. To investigate the molecular regulation of F-actin, we identified that tail, Achilles, and plantaris tendons express three isoforms in common: Tpm1.6, 3.1, and 4.2. Tpm3.1 associates with F-actin in native and primary tenocytes. Tpm3.1 inhibition reduces F-actin, leading to decreases in tenogenic expression, increases in chondrogenic expression, and enhancement of protease expression in mouse and human tenocytes. These expression changes by Tpm3.1 inhibition are consistent with tendinosis progression. A further understanding of F-actin regulation in musculoskeletal cells could lead to new therapeutic interventions to prevent alterations in cellular phenotype during disease progression.