SMAD6 and Osteopenia: SMAD6 prefers to inhibit BMP signaling, whereas SMAD7 inhibits TGF-β and BMP signaling.277 Like Noggin, SMAD6 mutations in humans also cause craniosynostosis due to the augmentation of BMP signaling.278 Smad6 transgene blocked BMP activation and led to osteopenia and dwarfism in mice.279Smad6-null mice exhibited axial and appendicular skeletal development defects, with an expanded hypertrophic zone attributed to increased BMP responsiveness.280 Smad6 also recruits Smurf1 to ubiquitinate and degrade Runx2 to inhibit osteoblast differentiation.281 In contrast, SMAD7 might be anabolic for bone.