Rationale: Monocytes play critical roles in the pathogenesis of arthritis by contributing to the inflammatory response and bone erosion. Among genes involved in regulating monocyte functions, miR-146a negatively regulates the inflammatory response and osteoclast differentiation of monocytes. It is also the only miRNA reported to differentially regulate the cytokine response of the two classical Ly6C^high and non-classical Ly6C^low monocyte subsets upon bacterial challenge. Although miR-146a is overexpressed in many tissues of arthritic patients, its specific role in monocyte subsets under arthritic conditions remains to be explored. Methods: We analyzed the monocyte subsets during collagen-induced arthritis (CIA) development by flow cytometry. We quantified the expression of miR-146a in classical and non-classical monocytes sorted from healthy and CIA mice, as well as patients with rheumatoid arthritis (RA). We monitored arthritis features in miR-146a^-/- mice and assessed in vivo the therapeutic potential of miR-146a mimics delivery to Ly6C^high monocytes. We performed transcriptomic and pathway enrichment analyses on both monocyte subsets sorted from wild type and miR-146a^-/- mice. Results: We showed that the expression of miR-146a is reduced in the Ly6C^high subset of CIA mice and in the analogous monocyte subset (CD14⁺CD16^-) in humans with RA as compared with healthy controls. The ablation of miR-146a in mice worsened arthritis severity, increased osteoclast differentiation in vitro and bone erosion in vivo. In vivo delivery of miR-146a to Ly6C^high monocytes, and not to Ly6C^low monocytes, rescues bone erosion in miR-146a^-/- arthritic mice and reduces osteoclast differentiation and pathogenic bone erosion in CIA joints of miR-146a^+/+ mice, with no effect on inflammation. Silencing of the non-canonical NF-κB family member RelB in miR-146a^-/- Ly6C^high monocytes uncovers a role for miR-146a as a key regulator of the differentiation of Ly6C^high, and not Ly6C^low, monocytes into osteoclasts under arthritic conditions. Conclusion: Our results show that classical monocytes play a critical role in arthritis bone erosion. They demonstrate the theranostics potential of manipulating miR-146a expression in Ly6C^high monocytes to prevent joint destruction while sparing inflammation in arthritis.

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