RT Journal Article SR Electronic T1 A novel disease-modifying osteoarthritis drug candidate targeting Runx1 JF Annals of the Rheumatic Diseases JO Ann Rheum Dis FD BMJ Publishing Group Ltd and European League Against Rheumatism SP annrheumdis-2012-201745 DO 10.1136/annrheumdis-2012-201745 A1 Fumiko Yano A1 Hironori Hojo A1 Shinsuke Ohba A1 Atsushi Fukai A1 Yoko Hosaka A1 Toshiyuki Ikeda A1 Taku Saito A1 Makoto Hirata A1 Hirotaka Chikuda A1 Tsuyoshi Takato A1 Hiroshi Kawaguchi A1 Ung-il Chung YR 2012 UL http://ard.bmj.com/content/early/2012/10/04/annrheumdis-2012-201745.abstract AB Objectives To identify a new disease-modifying osteoarthritis drug (DMOAD) candidate that can effectively repair cartilage by promoting chondrogenic differentiation and halt osteoarthritis (OA) progression by suppressing aberrant hypertrophy. Methods We screened 2500 natural and synthetic small compounds for chondrogenic agents via four steps using the Col2GFP-ATDC5 system and identified a small thienoindazole derivative compound, TD-198946, as a novel DMOAD candidate. We tested its efficacy as a DMOAD via intra-articular injections directly into the joint space in a surgically-induced mouse model of OA both at the onset (prevention model) and 4   weeks after (repair model) OA induction. The downstream molecules were screened by microarray analysis. We further investigated the mechanism of the drug action and its molecular target using in vitro and in vivo assays. Results TD-198946 strongly induced chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. When administered directly into the joint space, TD-198946 successfully prevented and repaired degeneration of the articular cartilage. TD-198946 exerted its effect through the regulation of Runx1 expression, which was downregulated in both mouse and human OA cartilage compared with normal tissue. Conclusions Our data suggest that TD-198946 is a novel class of DMOAD candidate, and that targeting Runx1 will provide a promising new approach in the development of disease-modifying drugs against OA.