OBJECTIVE.: The collagen type II specific monoclonal antibodies M2139 and CIIC1, induce arthritis in vivo and degrade bovine cartilage explants in vitro, whereas the monoclonal antibody CIIF4 is non-arthritogenic, and prevents arthritis development when given in combination with M2139 and CIIC1. To determine the nature of protective capacity of CIIF4 antibody, we examined the effects of addition of CIIF4 to cartilage explants cultured with M2139 and CIIC1 in vitro. METHODS.: Bovine cartilage explants were cultured in the presence of M2139 and CIIC1 with or without CIIF4. Histological changes were examined, and chemical changes to collagens and proteoglycans were assessed by Fourier Transform Infrared Microspectroscopy (FTIRM). Fresh cartilage and cartilage freeze-thawed to kill chondrocytes and with or without the addition of GM6001, a broad spectrum inhibitor of matrix metalloproteinases (MMP) were compared using FTIRM analysis. RESULTS.: Whereas M2139 and CIIC1 caused progressive degradation of the cartilage surface and loss of CII, even in the absence of viable chondrocytes, CIIF4 did not cause cartilage damage, and when given with the arthritogenic mAbs prevented damage and permitted matrix regeneration, a process that required viable chondrocytes. Inhibition of MMP activity reduced cartilage damage but did not mimic the effects of CIIF4. CONCLUSIONS.: CII reactive antibodies can cause cartilage damage, or be protective in vivo and in vitro, depending on their epitope specificity. As CII antibodies of similar specificity occur also in human RA, more detailed studies should unravel regulatory mechanisms operating at the effector level of arthritis pathogenesis.