Stress deprivation of tendon explants or Tpm3.1 inhibition in tendon cells reduces F-actin to promote a tendinosis-like phenotype

Inguito, Kameron L.
Schofield, Mandy M.
Faghri, Arya D.
Bloom, Ellen T.
Heino, Marissa
West, Valerie C.
Ebron, Karl Matthew M.
Elliot, Dawn M.
Parreno, Justin
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Molecular Biology of the Cell
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.
This article was originally published in Molecular Biology of the Cell. The version of record is available at: This article will be embargoed until 02/01/2023.
Inguito, Kameron L., Mandy M. Schofield, Arya D. Faghri, Ellen T. Bloom, Marissa Heino, Valerie C. West, Karl Matthew M. Ebron, Dawn M. Elliott, and Justin Parreno. “Stress Deprivation of Tendon Explants or Tpm3.1 Inhibition in Tendon Cells Reduces F-Actin to Promote a Tendinosis-like Phenotype.” Edited by Alex Dunn. Molecular Biology of the Cell 33, no. 14 (December 1, 2022).