A novel disease-modifying osteoarthritis drug candidate targeting Runx1
- Fumiko Yano1,
- Hironori Hojo1,
- Shinsuke Ohba1,
- Atsushi Fukai2,
- Yoko Hosaka2,
- Toshiyuki Ikeda2,
- Taku Saito2,
- Makoto Hirata2,
- Hirotaka Chikuda2,
- Tsuyoshi Takato2,
- Hiroshi Kawaguchi2,
- Ung-il Chung1,3
- 1Center for Disease Biology and Integrative Medicine , The University of Tokyo, Tokyo, Japan
- 2Sensory and Motor System Medicine, The University of Tokyo, Tokyo, Japan
- 3Department of Bioengineering, The University of Tokyo, Tokyo, Japan
- Correspondence to Dr Fumiko Yano, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;
- Accepted 11 September 2012
- Published Online First 5 October 2012
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.