bone morphogenetic proteins

The activity of BMPs was first demonstrated in the 1960s (Urist MR 1965). The BMPs were originally named for their ability as growth factors to stimulate bone formation in vertebrates. However, this is not their only function. For example, bone morphogenetic protein 2 (BMP2), in addition to its ability to stimulate bone formation, also has the ability to differentiate stem cells into cartilage tissue. In stem cells from the synovial membrane, the growth factor BMP2 reacts synergistically with the growth factor TGF-beta. BMP2 and TGF-beta react differently to the presence of the glucocorticoid dexamethasone.

Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor (TGF) superfamily. The BMPs are a component of the TGF-beta signaling pathway, one of the basic signaling systems for communication between cells. The BMPs are also known as paracrine signaling molecules. To date, about 20 members of the BMP family have been identified and characterized.

The BMPs and the associated TGF-β signaling pathway are highly conserved and are found in organisms as diverse as humans, fruit flies (Drosophila), zebrafish and nematodes (e.g. Caenorhabditis elegans). The TGF-beta signaling pathway plays an important role in many phases of development in all these organisms. For example, in the early development of the fruit fly embryo, this signaling pathway controls the division of the body into the abdominal and dorsal halves. The genes that code for BMPs in humans are: BMP1 (bone morphogenetic protein 1), BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15, GDF10

The role of BMPs in embryonic development and cellular functions in postnatal and adult animals has been extensively studied in recent years. Signal transduction studies have shown that Smad1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction.

Studies in transgenic and knockout mice as well as in animals and humans with naturally occurring mutations in BMPs and related genes have shown that BMP signaling plays a critical role in the development of the heart, nervous system and cartilage. 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 used in various therapeutic interventions such as bone defects, non-healing fractures, spinal fusion, osteoporosis and root canal surgery.

BMPs signal via serine/threonine kinase receptors, which consist of type I and type II subtypes. Three type I receptors have been shown to bind BMP ligands, type IA and type IB BMP receptors (BMPR-IA or ALK-3 and BMPR-IB or ALK-6) and type IA activin receptors (ActR-IA or ALK-2) (Koenig, B.B. et al. 1994; ten Dijke P et al. 1994). Three type II receptors for BMPs have also been identified, namely the type II BMP receptor (BMPR-II) and the type II and IIB activin receptors (ActR-II and ActR-IIB). While BMPR-IA, IB and II are specific for BMPs, ActR-IA, II and IIB are also signaling receptors for activins. These receptors are expressed differently in different tissues. Type I and II BMP receptors are both essential for signal transduction. After ligand binding, they form a heterotetramerically activated receptor complex consisting of two pairs of a type I and type II receptor complex (Moustakas A et al. 2002). The type I BMP receptor substrates include a protein family, the Smad proteins, which play a central role in the transmission of the BMP signal from the receptor to the target genes in the cell nucleus. Smad1, 5 and 8 are phosphorylated by BMP receptors in a ligand-dependent manner. Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal progenitor cell line C2C12. Upon release from the receptor, the phosphorylated Smad proteins bind to the cognate protein Smad4, which acts as a common partner. This complex migrates into the nucleus and is involved in gene transcription together with other transcription factors Significant progress has been made in recent years in understanding the in vivo functions of BMP ligands, receptors and signaling molecules (Chen D et al. 2004).

Two BMP bone substitutes, BMP2 (InFuse®) and BMP7 (OP1®), have been developed as products for the healing of nonunion fractures of long bones and lumbar spinal fusion in humans. The approval of BMP2 and BMP7-based products for clinical use supports the notion that the signals responsible for bone formation at ectopic sites may provide a basis for therapeutics for bone healing and regeneration.

BMPs do not only influence bone formation. In frogs and also in humans, they lead to apoptosis (programmed cell death) and thus to the regression of the cilia and the formation of fingers.

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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
3. Moustakas A et al. (2002) From mono- to oligo-Smads: the heart of the matter in TGFbeta signal transduction. Genes Dev 16: 67-871.
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5. 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
6. Urist MR (1965) Bone formation by autoinduction. Science 150: 893-899.