Bone Morphogenetic Proteins

Abstract

Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor beta (TGFbeta) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smad1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and related genes have shown that BMP signaling plays critical roles in heart, neural and cartilage development. BMPs also play an important role in postnatal bone formation. BMP activities are regulated at different molecular levels. Preclinical and clinical studies have shown that BMP-2 can be utilized in various therapeutic interventions such as bone defects, non-union fractures, spinal fusion, osteoporosis and root canal surgery. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue. BMPs are members of the TGFbeta superfamily. The activity of BMPs was first identified in the 1960s (Urist, M.R. (1965) "Bone formation by autoinduction", Science 150, 893-899), but the proteins responsible for bone induction remained unknown until the purification and sequence of bovine BMP-3 (osteogenin) and cloning of human BMP-2 and 4 in the late 1980s (Wozney, J.M. et al. (1988) "Novel regulators of bone formation: molecular clones and activities", Science 242, 1528-1534; Luyten, F.P. et al. (1989) "Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation", J. Biol. Chem. 264, 13377-13380; Wozney, J.M. (1992) "The bone morphogenetic protein family and osteogenesis", Mol. Reprod. Dev. 32, 160-167). To date, around 20 BMP family members have been identified and characterized. BMPs signal through serine/threonine kinase receptors, composed of type I and II subtypes. Three type I receptors have been shown to bind BMP ligands, type IA and IB BMP receptors (BMPR-IA or ALK-3 and BMPR-IB or ALK-6) and type IA activin receptor (ActR-IA or ALK-2) (Koenig, B.B. et al. (1994) "Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells", Mol. Cell. Biol. 14, 5961-5974; ten Dijke, P. et al. (1994) "Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4", J. Biol. Chem. 269, 16985-16988; Macias-Silva, M. et al. (1998) "Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2", J. Biol. Chem. 273, 25628-25636). Three type II receptors for BMPs have also been identified and they are type II BMP receptor (BMPR-II) and type II and IIB activin receptors (ActR-II and ActR-IIB) (Yamashita, H. et al. (1995) "Osteogenic protein-1 binds to activin type II receptors and induces certain...

Differential expression of a BMP4 reporter allele in anterior fungiform versus posterior circumvallate taste buds of mice

“…BMPs regulate many cellular processes, including differentiation, proliferation, apoptosis, adhesion, and migration (reviewed by Chen, 2004) [40]. In the developing taste organs of embryos, BMP4 is precisely co-expressed with Shh in taste placodes [41].…”

Osseointegration of Titanium Prostheses on the Stapes Footplate

“…BMP induces osteogenic cell differentiation in vitro as well as bone defect healing in vivo. Enhancing the binding of endogenic BMP by collagen matrices with CS creates an osteogenic microenvironment that allows multipotent cell progenitors to migrate to the area of injury and to proliferate and differentiate toward the osteogenic lineage (Chen et al 2004). The BMP activity is related to the cytokine's ability to mobilize the patient's own stem/progenitor cells to result in the healing process; this ability was demonstrated for human (Chaudhary et al 2004) and for rat bone marrow stromal cells (Hu et al 2005).…”

Overexpression of the transcription factor Msx1 is insufficient to drive complete regeneration of refractory stage Xenopus laevis hindlimbs

“…One such pathway involves signaling by bone morphogenetic proteins (Bmps: Beck et al, 2003Beck et al, , 2006Pearl et al, 2008), which form a subset of the large Tgf-␤ family of secreted molecules. Bmp signaling regulates a diverse array of processes including tissue specification and cellular proliferation, differentiation, and apoptosis (reviewed in Chen et al, 2004). Bmps 2, 4, and 7 are involved in the processes of tetrapod limb development, and are known to regulate apical epidermal ridge (AER) development, digit specification, apoptosis, and limb outgrowth (reviewed in Robert, 2007).…”