Background/Purpose:  Juvenile Idiopathic Arthritis (JIA) is a multifactorial autoimmune disease characterized by the accumulation of various immune cells, including monocytes, in the joint synovial fluid (SF). Joint function is severely affected in JIA patients due to fluid accumulation and bone damage. The molecular mechanisms underlying JIA and other autoimmune diseases still remain largely elusive. We aimed to create more insight into disease pathogenesis by performing epigenetic and gene expression profiling of CD14⁺ cells derived from the site of inflammation of JIA patients.

Methods:  Chromatin immunoprecipitation sequencing was performed to determine the (super-)enhancer repertoire of JIA patient SF-derived monocytes. Gene expression of SF-derived monocytes was analyzed using RNA-sequencing. Osteoclastogenesis of monocytes was assessed by osteoclast differentiation assays followed by tartrate-resistant acid phosphatase (TRAP) staining and bone resorption measurements.

Results:  The (super-)enhancer profile of JIA patient-derived monocytes demonstrated that osteoclast-related genes are associated with an increased enhancer or super-enhancer in JIA compared to healthy control (HC) monocytes, suggesting that the osteoclast pathway might play a crucial role in JIA monocytes. This is in agreement with the observation that osteoclast-associated genes are enriched in genes that are upregulated in JIA SF-derived monocytes, indicating that osteoclast differentiation might be increased. Indeed, differentiation of HC monocytes in the presence of SF enhanced the formation of osteoclasts.

Conclusion:  Our results indicate that monocytes obtained from the inflammatory site of JIA patients display increased osteoclastogenesis, resulting in more bone degradation. This enhanced osteoclast differentiation is likely to be the consequence of the inflammatory environment present in the joint. Altogether, therapies aimed at inhibiting the differentiation of monocytes into osteoclasts, for example by inhibiting inflammatory mediators present in the SF, might reduce bone loss and thus improve joint function in JIA patients.