Transcriptional regulation of synovial fibroblasts in arthritis

A major research focus of our laboratory is to elucidate the role of the group C of the SOX transcription factor family, which consists of three members Sox4, Sox11 and Sox12. We initially showed that the SOXC genes exhibit functionally redundancy in the fibroblasts located in the synovial lining of the joint capsule to promote cartilage and bone degeneration in joint diseases, such as rheumatoid arthritis and osteoarthritis. Subsequently, we utilized genome wide approaches such as ChIP-seq and RNA-seq to show that SOXC proteins and the NF-kappaB signaling transcription factor, RELA/p65 act a co-factors that activate pro-inflammatory gene expression and thereby exacerbate inflammation-induced joint degeneration in arthritic diseases. Our goal for this project is to identity upstream and downstream targets of the newly identified SOXC/RELA molecular axis and block its activation for therapeutic development.

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Epigenetic memory in synovial fibroblasts

Synovial fibroblasts are the primary promoters of chronic inflammation in arthritic joints. We are currently using genome wide approaches such as ChIP-seq, ATAC-seq, single cell and bulk RNA-seq to study inflammation-induced transcriptomic and epigenetic changes in the synovial fibroblasts of arthritic joints. We published that synovial fibroblasts develop a long-term epigenetic memory upon exposure to inflammation, which in turn enables them to retain a persistently pathological phenotype, even after resolution of inflammation. We are excited about uncovering the mechanisms underlying the establishment of long-term inflammatory memory in synovial joints.

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Mechanisms underlying the pathology of hand osteoarthritis

Hand osteoarthritis (OA) is a highly prevalent form of arthritis, which profoundly effects the ability of the patients to perform simple daily tasks. Despite the amplitude of this health problem, our understanding of the pathophysiology of hand OA is seriously lagging. The goal of our most recent research program is to fill this gap in knowledge. In this direction we developed one of the first genetic mouse model for hand OA. In unpublished studies form the synovial fibroblasts of hand OA patients and our new mouse model, we identified key signaling pathways that differentiate hand OA from other joint OA. We are now focusing on identifying druggable genes and pathways for hand OA therapy.