| description |
A number of human diseases, including arthritis and atherosclerosis, shows characteristic predilection for specific anatomic locations. We studied the role of site-specific stromal cell biology in defining location-specific pathology in arthritis as a model disease. We demonstrate that synovial fibroblasts (SF), the main resident cells of the synovium, exhibit large anatomic differences in their transcriptomes. Site-specific HOX gene signatures determined joint-specific origins of murine and human SF and synovial tissues. We show that alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Transcriptional diversity translated into joint-specific phenotypes of SF with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNFα, creating a unique microenvironment in each joint. These findings deeply alter the current understanding of synovial biology and offer a concept that local stroma governs positional disease patterns not only in arthritis but any disease with a prominent stromal component. |