Background/Purpose: Focal articular bone erosion in rheumatoid arthritis (RA) is mediated by osteoclasts and repair of erosion by osteoblasts is uncommon, despite the use of potent anti-inflammatory therapies. TNF treatment of primary calvarial osteoblasts from Wnt reporter (Top-gal) mice suppresses Wnt signaling activity in these cells, altering a pathway critical for osteoblast differentiation and function. Additional mechanisms inhibiting bone formation likely contribute to the persistence of articular erosion in this disease. We have shown in an animal model of RA that in the setting of resolving inflammation, repair of articular bone erosion can occur, accompanied by alterations in expression of components of the Wnt signaling pathway. MicroRNAs (miRNAs) are important regulators of skeletal remodeling and several miRNAs, including miR-23b and miR-155, have been shown to play a role in RA pathogenesis. Since miRNAs can regulate both inflammation and bone remodeling, we hypothesized that they might play a regulatory role in bone erosion in RA.

Methods: To address the potential role of miRNAs in these pathogenic events, we used a modification of the serum transfer model of RA for the study of bone erosion development and repair in which inflammation is induced, then allowed to resolve. We performed Fluidigm high-throughput expression profiling of 750 miRNAs in pooled synovial samples from non-arthritic and arthritic mice (peak inflammation, day 10), as well as mice with resolving inflammation (day 21). We also performed gene array (Affymetrix) analysis in these same RNA samples. We analyzed and compared gene and miRNA array expression, and performed gene ontology analyses to identify important pathways.

Results: We performed a principle component analysis that revealed three distinct sets of miRNAs with expression patterns that were significantly different between synovium from non-arthritic mice and mice with peak inflammation and resolving inflammation. We then compared miRNA and gene expression patterns and found 796 up-regulated genes in arthritic compared with non-arthritic synovium that are predicted targets of down-regulated miRNAs (1.5 fold or >). Relevant pathways from gene ontology analysis included extracellular matrix organization, cell cycle, inflammation, and blood vessel and bone development. We also found 639 genes to be down-regulated that are predicted targets of up-regulated miRNAs (1.5 fold or >) in arthritic compared with non-arthritic synovium. Gene ontology analysis included genes in the TGFß signaling pathway and genes regulating skeletal development. Finally, expression of several miRNAs was significantly altered during the resolution phase compared with peak inflammation, and some of these miRNAs may also regulate skeletal pathways.

Conclusion: In this murine model of bone erosion development and repair, we have identified miRNAs and associated genes whose relative expression is altered according to stage of inflammation/erosion. Further study of these miRNAs and regulated pathways may prove fruitful for elucidating mechanism and developing therapeutic strategies for bone remodeling.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-of-micrornas-in-the-regulation-of-inflammation-and-bone-erosion-in-rheumatoid-arthritis/