Fig. 3.

Signaling pathways of TGF-β and BMP. The members of the TGFβ and BMP families are involved in bone development, extracellular matrix and cartilage maturation. TGF-β and BMP bind to the extracellular domains of specific receptors and require SMAD proteins for signal transduction within cells. TGF-β and BMP act through heterodimer receptors made up of kinase proteins type I and II. After ligand binding to the receptor, the receptor forms homodimeric complexes, which can auto phosphorylate serine/threonine residues. This triggers a cascade of events involving the phosphorylation of the SMAD protein. The TGF-β pathway requires SMAD2 and SMAD3 which react with SMAD4 to create a heterocomplex. This complex enters the nucleus and controls transcription by binding to target gene promoters including SOX9 and other genes involved in the chondrogenesis mechanism. SMAD7 is an adaptor protein that recruits ubiquitin ligases, called Smurfs and binds them to the TGF-β receptor complex to promote its degradation through proteasomal and lysosomal pathways. Therefore, Smad7 plays a crucial role in a negative feedback cycle to control TGF-β activity. The BMP2 signal depends on SMAD1, 5 and 8. They bind SMAD4 to move into the core, where they induce the expression of RUNX2 and other genes leading to differentiation of osteoblasts and osteocytes