Ogerin induced activation of Gpr68 alters tendon healing

Abstract

Satisfactory outcomes after acute tendon injuries are hampered by a fibrotic healing response. As such, modulation of extracellular matrix deposition and remodeling represents an important intervention point to improve healing. During fibrosis, matrix is deposited and remodeled by activated fibroblasts and/or myofibroblasts. Recent work has demonstrated that Ogerin, a positive allosteric modulator of the orphan proton-sensing GPCR, GPR68, can modulate fibroblast ↔ myofibroblast dynamics in multiple fibroblast populations, including blunting myofibroblast differentiation and facilitating reversion of mature myofibroblasts to a basal fibroblast state in vitro. In the present study, we tested the ability of Ogerin to modulate tendon fibroblast ↔ myofibroblast behavior in vitro and in vivo. Consistent with prior work, Ogerin can both blunt TGF-β induced tenocyte → myofibroblast differentiation and partially revert mature myofibroblasts to a basal tenocyte state. However, Ogerin treatment from days 8–12 after tendon repair surgery did not inhibit myofibroblast differentiation, and Ogerin treatment from post-operative days 24–28 did not induce myofibroblast reversion. Moreover, while we expected Ogerin treatment from days 8–12 to impair healing due to blunted extracellular matrix formation, Ogerin treatment improved tendon mechanical properties and altered cell transcriptional profiles and communication patterns in a way that suggests accelerated remodeling and resolution of the repair response, identifying Ogerin as a novel therapeutic approach to improve the tendon healing process.