Signal transduction of bone morphogenetic proteins in osteoblast differentiation.

Bone morphogenetic proteins (BMPs) were initially identified by their ability to induce ectopic cartilage and bone formation 1. Upon cDNA cloning of BMP-2, BMP-3, and BMP-4, the predicted amino acid sequences revealed that BMPs (except BMP-1, which is a member of the astacin family of metalloproteases) are members of the transforming growth factor-β (TGF-β) superfamily 2, to which the TGF-βs, activins, nodal, and Mullerian inhibiting substance (MIS)/anti-Mullerian hormone (AMH) also belong 3. The structure of TGF-β family members, at least thirty-four of which are present in the human genome 4, consists of an amino-terminal signal sequence, a pro-domain, and their carboxy-terminal mature peptide that is released upon furin-mediated cleavage ( Fig. 1 , A ). The mature domain is highly conserved and has a characteristic 7-cysteine motif. The mature domain forms homodimers or heterodimers that are in most cases covalently linked by one disulphide bond. The BMP/growth and differentiation factors (GDFs) are the largest family that can be divided into multiple subgroups of highly structurally related proteins ( Fig. 1 , B ). TGF-β superfamily members have been identified in many animal species, including mice, zebra fish, and Xenopus, and in evolutionarily more separated species such as Drosophila and Caenorhabditis elegans . Fig. 1: The TGF-β superfamily. A: Schematic structure of a TGF-β superfamily member. Signal peptide (SigP), pro-domain, and mature peptide are indicated. B: Dendrogram of all human TGF-β superfamily members. The human chromosomal location of each gene is indicated. Consistent with their in vivo cartilage and bone-inducing activities, BMPs have been found to have important roles in directing the fate of mesenchymal cells; they stimulate differentiation into the osteoblast lineage and inhibit differentiation toward myoblasts 5. Subsequent studies have shown that BMPs, like other members of the TGF-β superfamily, are multifunctional proteins with many soft-target …