To determine the relationship between synovial inflammation and the concomitant occurrence of cartilage and bone erosion during conditions of variable inflammation using various Fcγ receptor knockout (FcγR^−/−) mice.

Antigen‐induced arthritis (AIA) was introduced in the knee joints of various FcγR^−/− mice and wild‐type controls. Joint inflammation and cartilage and bone destruction levels were determined by histologic analysis. Cathepsin K, RANKL, and osteoprotegerin (OPG) levels were detected by immunolocalization.

In FcγRIIb^−/− mice, which lack the inhibiting Fcγ receptor IIb, levels of joint inflammation and cartilage and bone destruction were significantly higher (infiltrate 93%, exudate 200%, cartilage 100%, bone 156%). AIA in mice lacking activating FcγR types I, III, and IV, but not FcγRIIb (FcR γ‐chain^−/− mice), prevented cartilage destruction completely. In contrast, levels of bone erosion and joint inflammation were comparable with their wild‐type controls. Of great interest, in arthritic mice lacking activating FcγR types I, II, and III, but not IV (FcγRI/II/III^−/− mice), levels of joint inflammation were highly elevated (infiltrate and exudate, 100% and 188%, respectively). Cartilage destruction levels were decreased by 92%, whereas bone erosion was increased by 200%. Cathepsin K, a crucial mediator of osteoclasts, showed a strong correlation with the amount of inflammation but not with the amount of activating FcγR, which was low in osteoclasts. RANKL, but not OPG, levels were higher in the inflammatory cells of arthritic knee joints of FcγRI/II/III^−/− mice versus wild‐type mice.

Activating FcγR are crucial in mediating cartilage destruction independently of joint inflammation. In contrast, FcγR are not directly involved in bone erosion. Indirectly, FcγR drive bone destruction by regulating joint inflammation.