title: TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation.
abstract: 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 β1 (TGFβ1), 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 TGFβ1- 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 TGFβ1 in dermal fibroblasts. TGFβ1 induced expression of TRPV4 proteins in a dose-dependent manner. Genetic ablation or pharmacological antagonism of TRPV4 channel abrogated Ca2+influx and both TGFβ1-induced and matrix stiffness-induced myofibroblast differentiation as assessed by1) α-smooth muscle actin expression/incorporation into stress fibers,2) generation of polymerized actin, and3) expression of collagen-1. We found that TRPV4 inhibition abrogated TGFβ1-induced activation of AKT but not of Smad2/3, suggesting that the mechanism by which profibrotic TGFβ1 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 TGFβ1 signals regulating dermal myofibroblast differentiation. These findings suggest that therapeutic inhibition of TRPV4 activity may provide a targeted approach to the treatment of scleroderma.
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, Maryland.
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, Maryland.
authors.forename: Rishov
authors.initials: R
authors.lastname: Goswami
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Merth
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland; and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cohen
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, Maryland.
authors.forename: Kai Y
authors.initials: KY
authors.lastname: Lei
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: David X
authors.initials: DX
authors.lastname: Zhang
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, Maryland; srahaman@umd.edu.
authors.forename: Shaik O
authors.initials: SO
authors.lastname: Rahaman
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D055119:Elastic Modulus / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000166:cytology* / Q000502:physiology*; D012867:Skin / Q000166:cytology; D013045:Species Specificity; D050916:TRPV Cation Channels / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D050916:TRPV Cation Channels; D053773:Transforming Growth Factor beta1; C486576:Trpv4 protein, mouse
keywords: TRPV4; calcium influx; dermal myofibroblast differentiation; matrix stiffness