Cysteine-rich 61 (Cyr61 or CCN1), a secreted protein from the CCN family, is an important proinflammatory cytokine. Migration and infiltration of mononuclear cells to inflammatory sites play a critical role in the pathogenesis of rheumatoid arthritis (RA). Monocyte chemoattractant protein-1 (MCP-1/CCL2) is the key chemokine that regulates migration and infiltration of monocytes. Here, we examined the role of CCN1 in monocyte migration, and CCL2 expression in osteoblasts. We found higher levels of CCN1 and CCL2 in synovial fluid from RA patients compared with levels from non-RA controls. We also found that the CCN1-induced increase in CCL2 expression is mediated by the MAPK signaling pathway and that miR-518a-5p expression was negatively regulated by CCN1 via the MAPK cascade. In contrast, inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA ameliorated articular swelling, cartilage erosion, and infiltration of monocytes in the ankle joints of mice with collagen-induced arthritis. Our study describes how CCN1 promotes monocyte migration by upregulating CCL2 expression in osteoblasts in RA disease. CCN1 could serve as a potential target for RA treatment.