Spondyloarthritis (SpA) is a family of chronic inflammatory diseases of the spine and peripheral joints. Systemic inflammation often precedes joint inflammation, although it is not known what precipitates tissue specificity. The mechanical stress theory posits that microtrauma associated with overloading at the enthesis initiates inflammation in the joint which fails to resolve in the context of systemic inflammation. Unpublished data from our lab show that the immunomodulatory transcription factor BHLHE40 is upregulated with murine SpA (TNFdARE) and during in vitro stretching of synovial fibroblasts. Pilot studies of BHLHE40 -/- mice show complete protection against collagen-induced arthritis. Human synovial and murine tendon scRNAseq data reveal that BHLHE40 is expressed in stroma and immune cells. This project aims to characterize BHLHE40 expression in different forms of human and murine arthritis, and in human Achilles tendons of mechanical load-associated pathologies. We will also study the role of BHLHE40 on the biomechanical properties of murine Achilles tendon entheses. We will then identify the cell type responsible for the arthritogenic effect of BHLHE40 by generating cell specific deletion in myeloid-, T- and entheis stromal cells. The identification of factors which transform mechanical stress to arthritis is a major leap forward in our understanding of SpA pathogenesis and could be a therapeutic target or biomarker for disease progression.