The expression of the collagen chaperone Hsp47 is regulated by mechanical loading through the YAP/TEAD pathway

Mechanical stimuli maintain tissue structure by regulating extracellular matrix (ECM) composition. Collagen, a major ECM component, requires heat shock protein 47 (Hsp47), a collagen-specific molecular chaperone, for proper folding and maturation. However, the molecular pathways linking mechanical stress to collagen biosynthesis through the regulation of Hsp47 expression are not fully understood. In this study, we demonstrate that the Hippo signaling pathway, mediated by the YAP/TEAD complex, directly controls Hsp47 transcription in response to mechanical loading. In a tail suspension mouse model, mechanical unloading induced YAP degradation, resulting in reduced Hsp47 expression and impaired collagen quality. Reloading reversed these changes, restoring both YAP and Hsp47 levels. Chromatin immunoprecipitation confirmed direct binding of TEAD1 to the Hsp47 promoter, establishing a mechanistic link between mechanical signals and Hsp47 regulation. In vitro, substrate stiffness increased Hsp47 expression in a TEAD1-dependent manner. Furthermore, unloading reduced the amount of collagen detected by Sirius Red staining in the soleus muscle. These findings identify the YAP/TEAD-Hsp47 axis as a direct mechanotransduction pathway linking mechanical cues to collagen homeostasis. By clarifying this link, we advance understanding of how tissues adapt to mechanical stress and identify a potential therapeutic target for diseases associated with ECM remodeling, including osteoporosis, muscle atrophy, and fibrosis.