Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions

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.

Synovial tissue research: a state-of-the-art review

“…Consistent with these findings, there are differences in DNA methylation and transcriptome signatures in FLS from different joints of RA patients as well as differences in FLS invasiveness depending on their positional memory. 65,66 Questions remain about where to biopsy within a given joint. In particular there have been concerns that mediators of inflammation may be differentially expressed in different parts of the same joint, especially between the cartilage pannus junction (CPJ) and non-CPJ sites which are known to behave differently.…”

Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound‐Guided Synovial Biopsies in Rheumatoid Arthritis

“…The fact that ultrasound-guided synovial biopsies may be performed in the clinic without a surgical suite and require minimal to no recovery time for the patient outweighs the smaller amount of tissue retrieved (23,29,41,45,(64)(65)(66)(67). In fact, in several countries in Europe, this technique is used to obtain synovial tissue for research purposes in a large number of patients without significant complications (34)(35)(36)(38)(39)(40)(68)(69)(70)(71)(72)(73). The procedure itself is well accepted by both patients and referring rheumatologists in the US, at rates similar to those observed by our European colleagues (34,36).…”

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

“…Indeed, it has now become apparent that there are subsets of synovial fibroblasts within the inflamed joint that display pro-and antiinflammatory phenotypes, with effects also dependent upon positional memory [83][84][85]. Indeed, it has now become apparent that there are subsets of synovial fibroblasts within the inflamed joint that display pro-and antiinflammatory phenotypes, with effects also dependent upon positional memory [83][84][85].…”