Cyromazine Rheumatoid arthritis is a chronic systemic inflammatory disease resulting in bone loss. Bone loss is exclusively driven by osteoclasts, which are bone-resorbing cells derived from myeloid cells. Osteoclast differentiation is regulated mainly by receptor activator of nuclear factor-kB and its ligand, RANKL. RANKL is predominantly expressed on osteoblasts and CZC24832 osteocytes. In pathological conditions, it can be expressed by other cells such as fibroblasts and T cells. In RA, inflammatory cytokines including tumor necrosis factor -a, interleukin -1b, and IL-6, have been found to enhance RANKL expression in synovial fibroblasts, which subsequently activates osteoclasts in joints. Additionally, these inflammatory cytokines can enhance osteoclastogenesis in cooperation with RANKL. As a result, excessive osteoclast activity causes bone loss in inflamed joints and throughout the body, leading to the loss of joint motion and increased risk of fractures in RA patients. However, further research is needed to fully elucidate the pathophysiology of osteoclast-driven bone loss in RA. SH3 domain-binding protein 2 is an adaptor protein, which is expressed primarily in immune cells including T cells, B cells, mast cells, neutrophils, and macrophages as well as osteoclasts. SH3BP2 interacts with various proteins, including SYK, PLCc, SRC, and VAV, and regulates intracellular signaling pathways in immune and skeletal systems. Previously we have reported that gainof-function mutations in SH3BP2 are responsible for cherubism. Cherubism is an autosomal dominant craniofacial disorder characterized by excessive jawbone destruction with swelling of the lower face. The jaw lesions consist mostly of fibroblastoid cells with a large number of tartrateresistant acid phosphatase -positive multinucleated giant cells, suggesting that the excessive jawbone resorption is caused by increased osteoclastogenesis. We have introduced a P416R SH3BP2 mutation into the mouse genome and established a knock-in mouse model for cherubism. Analysis of the mouse model has revealed that homozygous mutant mice spontaneously develop severe arthritis and osteopenia and that heterozygous mice exhibit mild osteopenia with no obvious inflammation.