The relation between in vivo increased osteoclastogenesis and systemic bone loss ACPAs was first demonstrated in 2012, following the comparison of the injection of purified human ACPAs, from the serum of patients with RA, into lymphocyte-deficient Recombination activating gene 1 (Rag1) –/– mice with control IgG injections. This evidence concerns the gene RAG1 and rheumatoid arthritis.