Abstract
Vocal fold (VF) fibrosis is a major cause of intractable voice-related disability and reduced quality of life. Excision of fibrotic regions is suboptimal and associated with scar recurrence and/or further iatrogenic damage. Non-surgical interventions are limited, putatively related to limited insight regarding biochemical events underlying fibrosis, and downstream, the lack of therapeutic targets. YAP/TAZ integrates diverse cell signaling events and interacts with signaling pathways related to fibrosis, including the TGF-β/SMAD pathway. We investigated the expression of YAP/TAZ following vocal fold injury in vivo as well as the effects of TGF-β1 on YAP/TAZ activity in human vocal fold fibroblasts, fibroblast-myofibroblast transition, and TGF-β/SMAD signaling. Iatrogenic injury increased nuclear localization of YAP and TAZ in fibrotic rat vocal folds. In vitro, TGF-β1 activated YAP and TAZ in human VF fibroblasts, and inhibition of YAP/TAZ reversed TGF-β1-stimulated fibroplastic gene upregulation. Additionally, TGF-β1 induced localization of YAP and TAZ in close proximity to SMAD2/3, and nuclear accumulation of SMAD2/3 was inhibited by a YAP/TAZ inhibitor. Collectively, YAP and TAZ were synergistically activated with the TGF-β/SMAD pathway, and likely essential for the fibroplastic phenotypic shift in VF fibroblasts. Based on these data, YAP/TAZ may evolve as an attractive therapeutic target for VF fibrosis.
Highlights
Vocal fold (VF) fibrosis is a major cause of intractable dysphonia commonly resulting in reduced quality of life as well as occupational and social limitations and profound healthcare expesnses[1,2,3,4]
We investigated the effects of TGF-β1 on Yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) activity in human vocal fold fibroblasts and the role of YAP/TAZ in fibroblast-myofibroblast transition
YAP/TAZ increased in response to iatrogenic vocal fold injury
Summary
Vocal fold (VF) fibrosis is a major cause of intractable dysphonia commonly resulting in reduced quality of life as well as occupational and social limitations and profound healthcare expesnses[1,2,3,4]. Activation of SMAD signaling does not occur in isolation and likely results in upregulation of R-SMAD inhibitors[23] This complexity and the potential for such therapies to disrupt endogenous SMAD inhibitory actions pose a significant challenge to therapeutic approaches targeting only SMADs for fibrosis. The Hippo pathway is modulated by soluble factors, cell–cell junctions, and ECM, these signals influence YAP/TAZ nuclear translocation and its role to support T EAD31–34. Several signaling pathways related to fibrosis, including Wnt and Rho, interact with YAP/TAZ further suggesting Hippo involvement in pathological fibrosis. YAP/TAZ binds Smad2/3 upon TGF-β stimulation and mediates nuclear translocation in mouse embryonic stem cells, HaCaT human keratinocytes, and human conjunctival fibroblasts[39,40,41]. YAP and TAZ are differentially activated in distinct cell types and their interaction with SMAD signaling appears variable
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