title: A novel disease-modifying osteoarthritis drug candidate targeting Runx1.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. yanof-ora@h.u-tokyo.ac.jp
authors.forename: Fumiko
authors.initials: F
authors.lastname: Yano
authors.forename: Hironori
authors.initials: H
authors.lastname: Hojo
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohba
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukai
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hosaka
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Taku
authors.initials: T
authors.lastname: Saito
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirata
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Chikuda
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Ung-il
authors.initials: UI
authors.lastname: Chung
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects*; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D015870:Gene Expression / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000494:pharmacology*; D007191:Indazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D006576:Heterocyclic Compounds, 4 or More Rings; D007191:Indazoles; D012333:RNA, Messenger; C493726:Runx1 protein, mouse; C581950:TD-198946