The serum CatK levels were increased in patients with active longstanding RA, which were significantly correlated with the severity of joint destruction. CatK deficiency largely prevented the cartilage erosion and bone destruction and reduced the joint inflammation in mice with TNF-α-mediated arthritis. Inhibition of CatK could suppress the cartilage degradation as well as the systemic and local bone loss to prevent joint destruction in preclinical RA models. Here, TNF is linked to arthritic joint disease.