Mechanical stretch facilitates tenomodulin expression to induce tenocyte migration via MAPK signaling pathway

Tenomodulin (Tnmd) is a type II transmembrane glycoprotein that regulates tendon development and matura-tion. Our previous study indicated that mechanical stretch could induce Tnmd expression to promote tenocyte migration, associated with reinforcement of fibrous actin (F-actin) stress fibers and chromatin decondensation. However, the detailed molecular mechanisms of this processes are far from clear. Activation of mitogen-activated protein kinase (MAPK) signaling occurs in response to various extracellular stimuli and controls a large number of fundamental cellular processes. The present study we investigated the influence of MAPK signaling on me-chanical stretch-induced Tnmd expression and its action way. Expression and activities of extracellular signal -related kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 MAPK (p38) were determined by Western blot. Cell migration was detected by Transwell assay. Immunofluorescence staining was used to detect F -actin stress fibers. Nuclear chromatin decondensation was detected by in situ DNaseI sensitivity assay. It was found that mechanical stretch promoted Tnmd expression by activating ERK1/2, JNK and p38 signaling. The inhibition of the ERK1/2, JNK or p38 repressed mechanical stretch-promoted tenocyte migration and mechanical stretch-induced reinforcement of F-actin stress fibers. However, only ERK1/2 and p38 inhibitor could repress mechanical stretch-induced chromatin decondensation, and the JNK inhibitor had no significant effect. More-over, latrunculin (Lat A), the most widely used reagent to depolymerize actin filaments, could inhibit the stretch -induced chromatin decondensation. Taken together, our findings elucidated a molecular pathway by which a mechanical signal is transduced via activation of MAPK signaling to influence reinforcement of F-actin stress fibers and chromatin decondensation, which could further lead Tnmd expression to promote tenocyte migration.

Automated summary

This study investigated the molecular mechanisms of mechanical stretch-induced Tnmd expression. It was found that mechanical stretch promoted Tnmd expression by activating ERK1/2, JNK, and p38 signaling, leading to reinforcement of F-actin stress fibers and chromatin decondensation. Only the inhibition of ERK1/2 and p38 had an effect on mechanical stretch-induced chromatin decondensation, while the JNK inhibitor did not. These findings elucidate a molecular pathway by which mechanical signals influence Tnmd expression to promote tenocyte migration, through activation of MAPK signaling and reinforcement of F-actin stress fibers and chromatin decondensation.