Gtf2ird1 -Dependent Mohawk Expression Regulates Mechanosensing Properties of the Tendon

Abstract

Mechanoforces experienced by an organ are translated into biological information for cellular sensing and response. In mam- mals, the tendon connective tissue experiences and resists physical forces, with tendon-specific mesenchymal cells called teno- cytes orchestrating extracellular matrix (ECM) turnover.Weshow that Mohawk (Mkx), a tendon-specific transcription factor, is essential in mechanoresponsive tenogenesis through regulation of its downstreamECMgenes such as type I collagens and pro- teoglycans such as fibromodulin both in vivo and in vitro. Wild-type (WT) mice demonstrated an increase in collagen fiber di- ameter and density in response to physical treadmill exercise, whereas in Mkx?/? mice, tendons failed to respond to the same mechanical stimulation. Furthermore, functional screening of the Mkx promoter region identified several upstream transcrip- tion factors that regulate Mkx. In particular, general transcription factor II-I repeat domain-containing protein 1 (Gtf2ird1) that is expressed in the cytoplasm of unstressed tenocytes translocated into the nucleus upon mechanical stretching to activate the Mkx promoter through chromatin regulation. Here, we demonstrate that Gtf2ird1 is essential for Mkx transcription, while also linking mechanical forces to Mkx-mediated tendon homeostasis and regeneration.