The fate of neural precursors in the developing brain is believed to be determined by intrinsic cellular programs and by external cues, including cytokines. BMPs (Bone Morphogenetic Proteins) are a large subclass (more than 20 members) of the TGF-beta (Transforming Growth Factor-Beta) super family that is active in many tissues under normal physiologic conditions, and are regulated through reversible interactions with extracellular antagonists, including noggin, chordin, follistatin and gremlin. These interactions determine the bioavailability of different BMPs for binding to their cognate receptors and activation of downstream responses.
BMPs themselves are further classified into several subgroups on the basis of sequence similarities and homology. These include BMP2, BMP4, decapentaplegic BMP5, BMP6, BMP7 and BMP8 (Ref. 1 & 2). Although originally named because of their ability to induce ectopic bone formation, cartilage condensation, chondrocyte maturation, and interdigital cell death, BMPs are involved in many developmental processes, including cell proliferation and differentiation, apoptosis, and intercellular interactions during morphogenesis (Ref. 3). Members of the BMP family function in a gene dosage–dependent manner during development and participate in ocular development. Therefore, mutations that alter the level of BMPs or alter the degree of BMP signaling are candidates to contribute to Axenfeld-Rieger syndrome and other conditions involving anterior segment malformation, elevated Intraocular Pressure (IOP), and glaucoma. Interestingly, some BMPs modulate tooth morphogenesis and Axenfeld-Rieger patients present with dental abnormalities (Ref. 4).
The action of BMP is mediated by heterotetrameric serine/threonine kinase receptors. Specific receptor subunits that bind to BMPs include BMPRI (BMP Receptor Type-I) and BMPRII (BMP Receptor Type-II) (Ref. 3). The BMPRI phosphorylates specific molecules in the cell cytoplasm, resulting in increased alkaline phosphatase activity, proteoglycan synthesis and collagen synthesis. Two specific forms of BMPRI include Type IA (ALK3, BRK1) and Type IB (TSK7L/ ALK2 (Activin Receptor-like Kinase 2), BRKII, RPK1), and are known to dimerize with BMPRII (ActRI (Activin Receptor Type-I), ActRII, ActRIIB, T-ALK) in the presence of BMP2, BMP4 and BMP7. BMP ligands can bind to either Type-I or Type-II receptor subunits independently, but both receptor types are required for high-affinity binding and signaling. Binding of BMP to its receptor complex results in the activation of BMPRI, which in turn phosphorylates SMAD1, SMAD5 and SMAD8 molecules. Upon phosphorylation, these BMP-specific SMADs form a complex with the co-SMAD, SMAD4 and translocate into the nucleus to activate transcription of specific genes. In the nucleus, the SMAD1-SMAD4 complex binds with low affinity to the GCCG or CAGA motif in the promoter regions of many BMP-responsive genes. They are also recruited to the promoters of BMP-responsive genes by high-affinity cofactors such as OAZ, which binds to the promoter of the Xvent2 gene. SMAD1 forms a complex with p300/CBP (CREB Binding Protein), FAST1, FAST2 (Forkhead Activin Signal Transducer), and STAT3 (Signal Transducers and Activators of Transcription-3), and this complex is involved in the transactivation of the glial fibrillary acidic protein gene, a marker for astrocyte differentiation. In addition, SMAD1 interacts with SIP1, the acute myelogenous leukemia protein, and the homeodomain transcription factor Hoxc8 (Ref. 5). Inhibitory SMAD proteins, SMAD6 and SMAD7, repress the action of BMP by inhibiting the receptor-mediated phosphorylation of SMAD1, SMAD5 or SMAD8 or by competing with SMAD4 for the binding to SMAD1, SMAD5 and SMAD8 (Ref. 6).
In the ectoderm, BMPs activate two biochemical pathways, one mediated by SMADs and a second mediated by the p38/MAPK (Mitogen-Activated Protein kinase) pathway downstream of TAK1 (TGF-Beta Activated Kinase-1) (Ref. 7). TAB1/2 (TAK1 Binding Protein 1/2) is a key effector in the activation of the NF-kappaB (Nuclear Factor-KappaB) and JNK (Jun N-terminal Kinase) pathways (Ref. 4). The transcriptional activation of TAB3 modulates the activity of TAK1, and might activate the NF-KappaB and JNK pathways. CalmKIV (Ca2+/calmodulin (Calm)-dependent Kinases) inhibits BMP signaling by activating a CBP-binding substrate, thereby preventing CBP from acting as a coactivator of BMP-specific target gene(s) that are required for hematopoiesis. When BMP, PKA (Protein Kinase-A) and CalmKIV pathways are activated simultaneously, they phosphorylate CREB (cAMP Responsive Element Binding Protein), which then binds to CBP and disrupts interactions between limiting amounts of CBP and the hematopoietic-specific DNA binding protein (Ref. 8).
BMPs initiate the recruitment of progenitor and stem cells towards the area of bone injury, stimulate both angiogenesis and the proliferation of stem cells from surrounding mesenchymal tissues, and promote maturation of stem cells into chondrocytes, osteoblasts and osteocytes. BMPs are also involved in the regulation of other biological processes unrelated to bone formation. They play an essential role in early vertebrate embryogenesis such as in mesoderm induction, limb development, stimulation of proteoglycan synthesis, alkaline phosphatase activity, collagen synthesis, osteocalcin expression in chondroblasts/osteoblasts and hematopoietic formation. Moreover, BMPs have drawn attention as possible regulators of CNS (Central Nervous System) development. BMPs (especially BMP2 and BMP4) play a pivotal role in the induction of vertebrate cardiac development and along with unknown factor(s) induced by DMSO (Dimethyl Sulfoxide) cooperatively transactivate the expression of Csx/NKX2.5 (NK2 Transcription Factor related, locus 5) and GATA4 through the MAPK pathway activated by TAK1 (Ref. 9 & 10). Recent research indicate that FPPH (Familial Primary Pulmonary Hypertension) and PPH (Sporadic Primary Pulmonary Hypertension) have a common etiology that is associated with the inheritance and/or spontaneous development of germline mutations in BMPRII gene suggesting that BMPs play an important role in the maintenance of normal pulmonary vascular physiology. BMP15 and its close homologue GDF9 (Growth Differentiation Factor-9) have recently been shown to be necessary for normal female fertility in mammals because of their exclusive expression in oocytes throughout folliculogenesis (Ref. 11 & 12). BMP7 has been implicated in such diverse processes as murine hind brain development, tooth development, nephrogenesis, eye development, and skeletal patterning.
The cloning of BMPs heralds an era where its clinical applications using suitable delivery systems in orthopedic surgery, dentistry, as well as plastic and reconstructive surgery is truly on the horizon. In spine surgery, especially during spinal fusions (Ref. 8), surgeons have demonstrated that a genetically-produced rhBMP2 (recombinant human BMP2) has the ability to stimulate a patient's own cells to make more bone. This finding has obvious beneficial implications for the treatment of bone fractures and bone defects in patients undergoing spinal fusion because it eliminates the need for bone transplantation from the pelvis and reduce the need for the implantation of spinal rods and screws. Although the most effective and optimal delivery system remain to be identified, it is clear that their use to heal or treat severe skeletal defects (axial, craniofacial and periodontal) will have enormous advantages over conventional treatments in clinical contexts. However, future investigations are required to establish the potential application of BMPs and TGF-beta for the prevention and therapy of both local and systemic bone loss (Ref. 13 & 14).
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- Bone morphogenetic proteins induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1 and cardiac transcription factors Csx/Nkx-2.5 and GATA-4. Monzen K, Shiojima I, Hiroi Y, Kudoh S, Oka T, Takimoto E, Hayashi D, Hosoda T, Habara-Ohkubo A, Nakaoka T, Fujita T, Yazaki Y, Komuro I. Mol Cell Biol. 1999 Oct;19(10):7096-105.
- Early stage-specific inhibitions of cardiomyocyte differentiation and expression of Csx/Nkx-2.5 and GATA-4 by phosphatidylinositol 3-kinase inhibitor LY294002. Naito AT, Tominaga A, Oyamada M, Oyamada Y, Shiraishi I, Monzen K, Komuro I, Takamatsu T. Exp Cell Res. 2003 Nov 15;291(1):56-69.
- Integral role of GDF-9 and BMP-15 in ovarian function. Otsuka F, McTavish KJ, Shimasaki S. Mol Reprod Dev. 2011 Jan;78(1):9-21.
- A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: its role in regulating granulosa cell mitosis.Otsuka F, Shimasaki S. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8060-5.
- Transforming growth factor-beta isoforms and the induction of bone formation: implications for reconstructive craniofacial surgery. Ripamonti U, Ferretti C, Teare J, Blann L. J Craniofac Surg. 2009 Sep;20(5):1544-55.
- Transforming growth factor-beta 1: induction of bone morphogenetic protein genes expression during endochondral bone formation in the baboon, and synergistic interaction with osteogenic protein-1 (BMP-7). Duneas N, Crooks J, Ripamonti U. Growth Factors. 1998;15(4):259-77.
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