Osteoarthritis occurs when synovial joints fail. Drugs that alter
the course of this disease, rather than simply alleviate symptoms,
are in clinical trials, but none have been approved yet in the
United States or the European Union. Johnson et al. describe the
discovery and characterization of a small molecule, kartogenin,
that improves joint function and promotes the regeneration of
cartilage in vivo in two rodent models of chronic and acute joint
injury. In vitro experiments indicated that kartogenin induces
the differentiation of mesenchymal stem cells into cartilage cells
(chondrocytes) and protects existing chondrocytes under pathophysiological
conditions. The authors found that kartogenin binds
filamin A, a protein that crosslinks actin filaments, through which
it regulates the nuclear localization of a transcription factor complex
of CBFb and RUNX2. Knockdown of either CBFb or RUNX2
with short-hairpin RNAs blocked the effect of kartogenin on cellular
differentiation. Kartogenin is the first drug reported to target
filamin A and as such may complement other osteoarthritis
drugs under development. (Science published online, doi:10.1126/
science.1215157, 5 April 2012)