Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis and bone destruction leading to irreversible joint deformity. The development of a novel treatment for RA aiming at joint repair is necessary. Recently, mesenchymal stem cells (MSCs) have been widely studied as a new therapeutic tool for the treatment of RA, due to their multipotency and also their immunosuppressive properties. We show here that MSCs inhibit osteoclast differentiation depending on the constitutive production of osteoprotegerin, a decoy receptor of receptor activator of nuclear factor kappa-B ligand (RANKL). Our results further indicate that MSCs are useful in RA treatment by preventing the progression of bone damage by inhibiting osteoclast differentiation. In addition, MSCs are likely to play important roles in bone metabolism and maintenance of joint formation. In conclusion, MSC is a promising tool for both anti-inflammation and bone repair for RA patients.