SMAD4: a gatekeeper of the bone

Bone morphogenic proteins (BMPs) and the Wnt signalling system are key regulators of skeletal development and homeostasis, but how these two regulators interact to drive osteogenesis is unclear. Now (p. 4974), Valerie Salazar, Roberto Civitelli and colleagues investigate the molecular mechanisms underlying BMP and Wnt/β-catenin interactions by ablating a key component of the greater transforming growth factor-β (TGF-β)/BMP signalling system, Smad4, in Osx1⁺ cells of the osteoblast lineage in mice. They show that ablation of Smad4 causes severe growth retardation, spontaneous fractures and a combination of features seen in a number of bone disorders. Markers for fully differentiated osteoblasts were found in the bones of Smad4 mutant mice, but multiple collagen-processing enzymes were absent, including an essential gene target of RUNX2, a master osteoblast transcription factor; these observations correlated with disorganised collagen matrix in the mice. Moreover, the collagen matrix was hypomineralised and Smad4-deficient bone cells were resistant to the matrix-mineralising effects of the canonical Wnt signalling pathway. Accordingly, the authors saw cleavage of β-catenin associated with increased caspase-3 activity, indicating that SMAD4 is necessary to maintain the integrity of the Wnt/β-catenin pathway in bone. Thus, SMAD4 has been identified as a key modulator of multiple signalling pathways that control bone mass through the function of bone-forming cells.