Joint destruction is the major clinic burden in patients with rheumatoid arthritis (RA). It is unclear, though, how this autoimmune disease progresses to the point of deterioration of the joint. Here, we report that in a mouse model of RA the upregulation of TLR2 expression and its α(2,3) sialylation in RANK+myeloid monocytes mediate the transition from autoimmunity to osteoclast fusion and bone resorption, resulting in joint destruction. The expression of α(2,3) sialyltransferases was significantly increased in RANK+TLR2+myeloid monocytes, and their inhibition or treatment with a TLR2 inhibitor blocked osteoclast fusion. Notably, analysis of our single-cell RNA-sequencing (scRNA-seq) libraries generated from RA mice revealed a novel RANK+TLR2−a subset that negatively regulated osteoclast fusion. Importantly, the RANK+TLR2+subset was significantly diminished with the treatments, whereas the RANK+TLR2−subset was expanded. Moreover, the RANK+TLR2−subset could differentiate into a TRAP+osteoclast lineage, but the resulting cells did not fuse to form osteoclasts. Our scRNA-seq data showed thatMafis highly expressed in the RANK+TLR2−subset, and the α(2,3) sialyltransferase inhibitor-inducedMafexpression in the RANK+TLR2+subset. The identification of a RANK+TLR2−subset provides a potential explanation for TRAP+mononuclear cells in bone and their anabolic activity. Further, TLR2 expression and its α(2,3) sialylation in the RANK+myeloid monocytes could be effective targets to prevent autoimmune-mediated joint destruction.