Inflammatory arthritis and tendinopathy are two distinct classes of musculoskeletal diseases for which treatments are ineffective in many patients. Our lab has postulated that excessive mechanical loading leads to inflammation induced joint and tendon tissue damage in these diseases. We have identified several mechanosensitive targets in joint fibroblasts, including the transcription factor BHLHE40. This indicates that mechanotransduction pathways play a role in joint and tendon function and that they might be key players in inflammatory arthritis and tendinopathy. Furthermore, previous research has highlighted members of the adhesion G protein-coupled receptor (aGPCR) family as potential novel therapeutic targets based on their ability to act as mechanotransducers and their accessibility as surface receptors. We will explore the expression of aGPCRs in human joint and tendon tissue, then develop tools to interfere with candidate aGPCRs. These tools will be used to understand the role of aGPCR in steady state mouse joint and tendon tissue. We will further use the tools to unravel the therapeutic potential of aGPCR manipulation in inflammatory arthritis and tendinopathy. The identification of novel therapeutic targets to address the unmet need of finding effective therapies for musculoskeletal disease could lead to a breakthrough in the treatment of these musculoskeletal diseases.