| First Author | Sharma S | Year | 2017 |
| Journal | Am J Physiol Cell Physiol | Volume | 312 |
| Issue | 5 | Pages | C562-C572 |
| PubMed ID | 28249987 | Mgi Jnum | J:241514 |
| Mgi Id | MGI:5902876 | Doi | 10.1152/ajpcell.00187.2016 |
| Citation | Sharma S, et al. (2017) TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation. Am J Physiol Cell Physiol 312(5):C562-C572 |
| abstractText | Scleroderma is a multisystem fibroproliferative disease with no effective medical treatment. Myofibroblasts are critical to the fibrogenic tissue repair process in the skin and many internal organs. Emerging data support a role for both matrix stiffness, and transforming growth factor beta1 (TGFbeta1), in myofibroblast differentiation. Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel activated by both mechanical and biochemical stimuli. The objective of this study was to determine the role of TRPV4 in TGFbeta1- and matrix stiffness-induced differentiation of dermal fibroblasts. We found that TRPV4 channels are expressed and functional in both human (HDF) and mouse (MDF) dermal fibroblasts. TRPV4 activity (agonist-induced Ca2+ influx) was induced by both matrix stiffness and TGFbeta1 in dermal fibroblasts. TGFbeta1 induced expression of TRPV4 proteins in a dose-dependent manner. Genetic ablation or pharmacological antagonism of TRPV4 channel abrogated Ca2+ influx and both TGFbeta1-induced and matrix stiffness-induced myofibroblast differentiation as assessed by 1) alpha-smooth muscle actin expression/incorporation into stress fibers, 2) generation of polymerized actin, and 3) expression of collagen-1. We found that TRPV4 inhibition abrogated TGFbeta1-induced activation of AKT but not of Smad2/3, suggesting that the mechanism by which profibrotic TGFbeta1 signaling in dermal fibroblasts is modified by TRPV4 may be through non-Smad pathways. Altogether, these data identify a novel reciprocal functional link between TRPV4 activation and TGFbeta1 signals regulating dermal myofibroblast differentiation. These findings suggest that therapeutic inhibition of TRPV4 activity may provide a targeted approach to the treatment of scleroderma. |
