SMAD2 and osteogenesis imperfecta: Although RUNX2 acts in a positive manner at early stages of osteoblast differentiation later it is inhibitory.(29) SMADs also have been shown to interact with RUNX2 by increasing its transcriptional activity.(30) OI mice have increased SMAD2 activation,(20) and this may be acting to maintain high levels of RUNX2 in the trabecular bone, thus impairing osteogenesis.