Gpr68 modulation of myofibroblast dynamics during tendon healing

Following injury, tendon heals via a fibrotic scar-mediated process. This fibrotic response impairs restoration of tendon structure and function, and there are currently no pharmacological approaches in standard use to enhance the healing process. While the overall cell environment during healing is dynamic and complex, myofibroblasts are key regulators of the healing process. During tendon healing, tenocytes undergo progressive activation and differentiation in to myofibroblasts. Myofibroblasts synthesize, contract and remodel the new extracellular matrix that is required for restoring tissue integrity. However, resolution of physiological healing requires clearance of myofibroblasts, either via apoptosis or reversion to a basal fibroblast/tenocyte state. Tissue fibrosis, including fibrotic tendon healing results from myofibroblast persistence. Indeed, we have previously shown that tendon scar tissue from both mouse and humans is enriched for myofibroblasts that take on an anti-apoptotic profile. As such, understanding the mechanisms, and identifying therapeutic approaches to modulate myofibroblast dynamics during healing would fill critical knowledge gaps. We and others have recently demonstrated that expression of the proton-sensing G-protein coupled receptor Gpr68/Ogr1 is decreased during tissue fibrosis. Moreover, small molecule activation of Gpr68 can modulate both myofibroblast differentiation and reversion of lung fibroblasts. Thus, in this high-risk high-reward proposal we will define the efficacy of pharmacological activation of Gpr68 to modulate tenocyte-myofibroblast dynamics during fibrotic tendon healing. In addition, our preliminary data suggest that changes in macrophage-specific Gpr68 expression during healing underpin several aspects of myofibroblast function. The on-going interaction between macrophages and myofibroblast is an important regulator of both physiological and fibrotic wound healing. Therefore, we will dissect the cell-type specifics functions of Gpr68 in modulating tendon healing, and in responding to small molecule activation of Gpr68. Successful completion of these studies will provide important fundamental information related to regulation of the cell environment during tendon healing, and will establish a novel pharmacological approach to enhance the tendon healing process.