Abstract
A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component.
Highlights
A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations
While fibroblasts from different tissues were long considered as functionally homogenous cells, involved primarily in extracellular matrix production, it is accepted that these cells perform a number of specialized functions[9,39,40]
Our work demonstrates that Synovial fibroblasts (SFs) from different anatomical locations exhibit significant differences in transcriptome, epigenome and function
Summary
A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns in arthritis but in any disease with a prominent stromal component. Synovial fibroblasts (SFs), the most abundant resident stromal cells of the synovium, are major local effectors of joint inflammation and destruction in arthritis, producing a variety of proinflammatory and matrixdegrading molecules[11,12,13]. This finding might underlie the joint-specific occurrence and severity of arthritis
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