Mechanism of action of Bone Morphogenic Protein 3 in the maintenance of Tissue Homeostasis

 

Dr. M.P. Santhosh Kumar¹*, T. Nandhini²

¹Reader, Department of Oral and Maxillofacial Surgery, Saveetha Dental College, Saveetha University 162, Poonamallee High Road, Velappanchavadi, Chennai 600077 Tamil Nadu, India

²Final year B.D.S. Saveetha Dental College

 

ABSTRACT:

Bone morphogenetic protein 3 (BMP 3), also known as osteogenin, is a protein in humans that is encoded by the BMP3 gene. It has the ability to regulate bone and cartilage development and it negatively regulates bone density. This article reviews the pathway in which bone morphogenic protein 3 acts upon and explains the mechanism of its action on the tissues.

 

 

INTRODUCTION:

Bone morphogenetic protein 3 (BMP 3), also known as osteogenin, is a protein in humans that is encoded by the BMP3 gene¹. The protein encoded by this gene is a member of the transforming growth factor beta superfamily. It, like other bone morphogenic proteins (BMP's) is known for its ability to induce bone and cartilage development^2,3,4. It is a disulfide-linked homodimer. BMP 3 negatively regulates bone density and is an antagonist to other BMP's in the differentiation of osteogenic progenitors^5,6. It is highly expressed in fractured tissues^7,8. This article reviews the pathway in which bone morphogenic protein 3 acts upon and explains the mechanism of its action on tissues.

 

MECHANISM OF ACTION

A member of the BMP family induces heterodimeric complex formation between two BMP receptors (BMPRs). The type II receptor kinase phosphorylates the type I receptor and subsequently activates intracellular signalling. On BMPR activation, Smad1–Smad5–Smad8 forms heterodimeric complexes with Smad4, which then translocate to the nucleus where they act directly and/or cooperate with other molecules to regulate the transcription of target genes (Fig 1).

 

Inhibitory Smad6–Smad7 specifically inhibits BMP signalling ^9,10,11,12. Antagonists, stimulatory and inhibitory co‐receptors, and Smurfs are actively involved in maintaining the BMP tissue homeostasis and regulate cross‐talk with other signalling pathways ^13,14.

 

Fig 1. Bone morphogenetic protein signaling

 

ActR, activin receptor; ALK, activin receptor‐like kinase; BAMBI, BMP and activin membrane‐bound inhibitor; BMP, bone morphogenetic protein; c‐kit, CD117, tyrosine kinase receptor; GPI, glycosylphosphatidyl inositol; HJV, haemojuvelin; P, phosphorylation; Ror2, receptor tyrosine kinase‐like orphan receptor 2; Smurf, Smad ubiquitin regulatory factor; Tsg, twisted gastrulation; Tyr, tyrosine; USAG1, uterine sensitization‐associated gene 1

 

Mechanism with which BMP-3 antagonizes TGF-h family ligand signaling in Xenopus embryos: (Fig 2) BMP-3 inhibit the mesoderm-inducing activities of both activin and BMP-4 by dipping the phosphorylation of R-Smads and  also that BMP 3 by itself is powerless to turn on BMP or activin R-Smads and consequently does not signal by a TGF-h pathway. Inhibition by BMP-3 knows how to be defeat by activate BMP or activin type I receptors or next to increased levels of ActRIIB. At last it was found, that BMP-3 binds to ActRIIB and also that this binding cannot be competed with addition of overload activin. The hypothesis is that BMP-3 is a novel TGF-h family antagonist which acts as intrusive with activin and BMP binding to ActRIIB, a type II receptor widespread to both signaling pathways. Beside by using this mechanism, BMP-3 is intelligent to adjust diverse developmental processes that are unnatural by both activin and BMP signaling at the level of the personality target cell, as long as the embryo with supplementary resources is able to adjust these signaling molecules ^15,16.

 

Fig. 2 Model of BMP-3 interaction with activin and BMP-4 in Xenopus embryos.

 

(A) Activin signals through ActRII–ActRI complexes to cause Smad2 phosphorylation and pattern dorsal mesodermal tissues. (B) BMPs signal through ActRII–BMPRI and BMPRII–BMPRI complexes to cause Smad1 phosphorylation and to pattern ventral mesoderm and epidermal tissues. (C) When activin and BMP-3 are both present, BMP-3 interferes with activin binding to ActRII, Smad2 activation and activin signal transduction are blocked. (D) When BMP-4 and BMP-3 are both present, BMP-3 interferes with BMP-4 binding to ActRII, the level of Smad1 phosphorylation and BMP signaling through ActRII is decreased. Since BMP-3 does not bind BMPRII, BMP-4 is still available to signal through the BMPRII–BMPRI complex to activate Smad1.

 

BMP-3 might be used to antagonize both activin and BMP signaling that BMP-3 antagonizes signaling by activin and BMP and identify the BMP-3 as an inhibitor of signal transmission next to the level of ligand obligatory to receptor. The effects of BMP-3 over expression on endogenous Smad phosphorylation in whole embryos is known. BMP-3 strongly summary the level of Smad2 phosphorylation other than that did not seem to result Smad1,5,8 activation in gastrula stage 10.5 embryos. These data were found with recent antisense morpholino experiment ¹⁷ by reinforcing the consequence of activin signaling during Smad2 for early on mesodermal patterning.

 

BMP-3 economically blocks endogenous activin signaling by declining Smad2 activation and excluding is not as successful at blocking endogenous Smad1,5,8 phosphorylation. This might be owing to the fact that BMPs be able to use both ActRII/B and BMPR-II to send out signals as activin utilize only ActRII/B. Consequently, if BMP-3 blocks signaling at ActRII/B, then BMPs possibly will still be cabable to encourage Smad1,5,8 phosphorylation during BMPR-II¹⁸. They are used to examine if BMP-3 will interact with ActRII/B.

 

Having recognized that BMP-3 blocks both activin and BMP at the receptor level, the receptor besieged by BMP-3 would have to be one ordinary to both the activin and BMP signaling pathways, mainly possible the type II activin receptor. ActRII/B have been reported  to join multiple ligands as well as BMP-2, BMP-7, GDF11 and activin ¹⁹. Interface of BMP-3 with ActRIIB, co-expressed BMP-3 with epitope tag ActRIIB (ActRIIB/Myc) in early Xenopus embryos in addition to that used the extracts of early gastrula stage animal halves for coimmuno precipitation assays.

 

Subsequently BMP-3 was co-precipitated with ActRIIB by the antimyc antibody.  Because BMP-3 and activin can both bind ActRIIB, it is probable these two proteins compete for binding to their common receptor most important to the inhibition of activin signaling. BMP-3 was co-expressed with ActRIIB/Myc in the absence or presence of growing amounts (2 ng, 4 ng, 6ng) of activin/HA along with protein extracts of gastrula stage animal halves be immuno precipitated with anti-myc antibody. BMP-3 bind the type II receptor, it cannot compete rotten by overload activin. The interaction may reproduce the ability of BMP-3 and activin to join to different sites on ActRIIB. Still if the two ligands do not compete for the same site on the receptor, binding of BMP-3 preclude signal transduction by the activin–ActRIIB complex²⁰. BMP-3 binding to type II receptor exaggerates the recruitment of type I receptor to the receptor complex. This complex is inactive and prevent activin signal transduction ²¹.

 

BMP-3 be a dorso-anteriorizing factor which antagonizes both activin and BMP-4 by obligatory to ActRII, their ordinary receptor, and intrusive with signal transduction. The interactions of BMP-3, activin and BMP-4 are outlined in Fig.2. When activin and BMP-3 be both present, if BMP-3 occupy ActRII, activin is disqualified, and an inactive receptor complex form which blocks Smad2 phosphorylation. Consequently, activin signaling in target tissues diminishes (Fig. 2 C). BMP-3 prohibited mesoderm arrangement by blocking activin phosphorylation of Smad2. When BMP-4 and BMP-3 are both present, if BMP-3 occupy ActRII, Smad1,5,8 phosphorylation cannot take place from end to end receptor complexes which contain ActRII (Fig. 2 D).

 

Nevertheless, since BMP-4 is not jumped by BMP-3, BMP-4 being capable to set off BMP signaling from side to side BMPR-II, allows BMP signaling in cells so as to articulate this BMP-specific type II receptor (Fig. 2 D). This is carried out with the initiation of the epidermal markers msx-1 and epidermal keratin and the time BMP-3 and BMP-4 are co-injected into animal caps and by scrutiny which is readily available is Smad1,5,8 signaling in whole embryos over expressing BMP-3. BMP-3 might not slab the activity Xnr1 (5), a ligand that signals during ActRIIB/Alk4 and require an EGF-CFC co-receptor ²².

 

One interesting possibility is with the intention of BMP-3 forming heterodimers with BMPs or activin, create dominant-negative ligands. It was observed that injected activin mRNA cannot set free the BMP-3 whole embryo phenotype. These results put forward that the BMP-3-antagonistic activity in experiments is doubtful to be owing to heterodimerization flanked by BMP-3 and activin²³. It is immobile that BMP-3/BMP-2/4 or BMP-3/activin heterodimers might form in Xenopus embryos and also contain their own receptor affinity that would permit for selective inhibition of a subset of TGF-h members²⁴.

 

The biological action of BMP-3 is because of its capability to adjust both activin and BMP signaling during ActRII. Selectively blocking ActRII can be a significant way to involve specific developmental process. In favour of example, overexpression of BMP-3 in whole embryo causes the formation of distended and ectopic cement glands. In recent years, a model have been put forth suggestive of that intermediate levels of BMP signaling in the ectoderm shows the way to cement gland formation, at the same time as high levels of BMP signaling encourage epidermis and low levels of BMP signaling effect in neural tissue^25,26.

 

Because BMP3 does not entirely block BMP signaling, cement gland tissue might be induced in embryos and animal caps owing to moderate levels of BMP signaling so as to happening throughout BMPRII. Supplementary support for this idea come as of the statement that BMP-3 and BMP-4 are both spoken in the just beginning cement gland²⁷, anywhere this regulatory interaction can occur. In gastrula stage embryos, BMP-3 transcript are set up throughout the marginal zone mesoderm anywhere they emerge to overlap by way of the expression of activin. This co-localization could permit BMP-3 to play a  vital role in restrict activin in a cell-specific manner, as a result that just the once BMP-3 binds to ActRII it is unavailable to hand on activin signals, ensure proper dorso-anterior mesodermal pattern. In adding up, BMP-3 expression overlap with BMP-4 expression in gastrula stage ectoderm anywhere BMP-3 may well take action to decrease BMP signaling, allow other BMP antagonists so as to expressed in Spemann’s organizer to productively encourage the full range of nervous system tissues²⁸. The capability of BMP-3 to encourage anterior neural tissue and restrain the mesoderm-inducing activities of both activin and BMP carry these ideas.

 

Because BMP-3 acts as an antagonist, it might require to be ablated in conjunction with other activin/BMP inhibitors in order to conclude its effects on embryonic development as have been freshly shown in triple morpholino knockdown experiments for noggin, chordin and follistatin ²⁹. It is also likely that another highly connected BMP family member (like BMP-3b/ GDF-10) compensate for the loss of BMP-3 in early embryos, or so as to the role of BMP-3 in Xenopus growth can be temporally limited to later stages. BMP-3 antagonized ventralizing BMPs excluding not nodal-like ligands. BMP-3 activate a TGF-h/activin-responsive reporter and also withdrawn BMP signaling downstream of the BMP type I receptor³⁰.

 

In conclusion, BMP-3 interfere with activin and BMP-4 binding to the type II activin receptor without activating R-Smads. In consequence, signaling during activin and BMP receptor complexes with the intention of exploit ActRII gets diminished. Accordingly, BMP-3 joins a growing family of TGF-h-like molecules as well as inhibin and lefty, which by asset of their capability to bind to TGF-h family receptors and co-receptors except not to make active signal transduction, serve up as modulators of growth factor activity throughout embryonic development. The effectiveness of BMP-3 because an antagonist of TGF-h superfamily signaling be furthermost for ligands which act openly throughout ActRII.

 

SUMMARY:

BMPs and activin put forth their belongings throughout a signaling cascade in that ligand binding bring collectively type I and type II receptor serine/threonine kinases on the cell surface ³¹. Just the once activate, the type II receptor phosphorylates the type I receptor, which in revolve phosphorylates receptor keeping pace Smad proteins (RSmads). These phosphorylated R-Smads then multifaceted with Smad4, translocate to the nucleus and mutually with other proteins regulate transcription of target genes. R-Smads 2,3 be phosphorylated to commence signaling by activin-like ligands whereas R-Smads1,5,8 are phosphorylated all through BMP signal transduction^32,33. Even as BMPs and activins be capable to attach to the same type II receptors (activin type II and IIB), they encompass separate type I receptors and it is from end to end the type I receptor/R-Smad pairings that a specific BMP or activin signal is propagate. Additionally, BMPs signal from end to end BMP-specific receptor complexes that exploit BMPRII, a receptor not used by activin-like ligands³⁴. The stretchy nature of these BMP and activin ligand–receptor .

 

BMP-3, have biological effects with the intention of being in opposition to those of osteogenic BMPs and TGF-h1 in a multiplicity of mammalian systems³⁵. In Xenopus embryos, unlike BMP-2, BMP-4 and BMP-7, that are potent ventralizing agents, BMP-3 induce dorsalization³⁶. These effects of BMP-3 are generally like to the BMP antagonists like noggin, chordin and follistatin, inhibit the mesoderm-inducing performance of BMP-2 and ADMP in animal cap assays. xBMP-3b, a molecule 83% homologous to xBMP-3, can also antagonize BMP like ligands in addition to nodal-like proteins³⁷. At the same time as these data recognize BMP-3 and BMP-3b as novel antagonists in the BMP/TGF-h-signaling cascade, they does not present any clues as to how they may put forth their belongings³⁸.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

REFERENCES:

1.     Cao X, Chen D. The BMP signaling and in vivo bone formation. Gene 2005;357:1–8.

2.     Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004;22:233–41.

3.     Sukhbir Lal Khokra, Bharat Parashar, Hitesh Kumar Dhamija, Manju Bala. Immunomodulators: Immune System Modifiers. Research J. Pharm. and Tech. 5(2): Feb. 2012; Page 169-174.

4.     Canalis E, Economides AN, Gazzerro E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 2003;24:218–35.

5.     Sandip N. Badeliya, Dhrubo Jyoti Sen. Bioreceptor Platform: A Macromolecular Bed for Drug Design. Asian J. Research Chem. 3(4): Oct. - Dec. 2010; Page 812-820.

6.     Namdev N., Upadhyay S. Challenges and approaches for Oral protein and peptide drug delivery. Research J. Pharm. and Tech. 9(3): Mar., 2016; Page 305-312.

7.     Seeherman H, Wozney JM. Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev 2005;16:329–45.

8.     Wozney JM. Overview of bone morphogenetic proteins. Spine. 2002 Aug 15;27(16S):S2-8.

9.     Nohe A, Keating E, Knaus P, Petersen NO. Signal transduction of bone morphogenetic protein receptors. Cell Signal 2004;16(3):291–9.

10.  Nishimura R, Hata K, Ikeda F, Matsubara T, Yamashita K, Ichida F, et al. The role of Smads in BMP signaling. Front Biosci 2003;8:s275–84.

11.  Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 2005;16:251–63.

12.  Hadeel Thaeir Al-Najeem, Arshad Noori Ghani Al-Dujaili. Assessment of Bone Morphogentic protein receptor 2 Level in Pulmonary Arterial Hypertension Disease . Research J. Pharm. and Tech. 2017; 10(8): 2614-2618.

13.  Kishigami S, Mishina Y. BMP signaling and early embryonic patterning. Cytokine Growth Factor Rev 2005;16:265–78.

14.  Kawabata M, Imamura T and Miyazono K. Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 1998; 9: 49–61.

15.  A. Ranganadha Reddy, T.C. Venkateswarulu, D. John Babu, N. Shyamala Devi. Homology Modeling, Simulation and Docking Studies of Tau-Protein Kinase. Research J. Pharm. and Tech. 7(3): Mar., 2014; Page 376-388.

16.  Gamer LW, Nove J, Levin M, Rosen V. BMP-3 is a novel inhibitor of both activin and BMP-4 signaling in Xenopus embryos. Developmental biology. 2005;285(1):156-68.

17.  Piepenburg, O., Grimmer, D., Williams, P.H., Smith, J.C. Activin redux: specification of mesodermal pattern in Xenopus by graded concentrations of endogenous activin B. Development 2004;131: 4977–86.

18.  Massague, J., Chen, Y.G., Controlling TGF-beta signaling. Genes Dev. 2000; 14: 627–44.

19.  Cheng, S.K., Olale, F., Bennett, J.T., Brivanlou, A.H., Schier, A.F. EGF-CFC proteins are essential coreceptors for the TGF-beta signals Vg1 and GDF1. Genes Dev. 2003; 17: 31–6.

20.  Subhadharsini S, Gopinath P. Detection of the Presence of Bbp Gene for Bone Bound Sialoprotein among Clinical isolates of Staphylococcus aureus. Research J. Pharm. and Tech 2016; 9(9):1430-1432.

21.  Schier, A.F. Nodal signaling in vertebrate development. Annu. Rev. Cell Dev. Biol. 2003; 19: 589–621.

22.  Wardle, F.C., Sive, H.L. What’s your position? The Xenopus cement gland as a paradigm of regional specification. BioEssays 2003;25: 717–26.

23.  Sive, H.L., Grainger, R.M., Harland, R.M., Early Development of Xenopus laevis: A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. 2000.

24.  Hino, J., Nishimatsu, S., Nagai, T., Matsuo, H., Kangawa, K., Nohno, T. Coordination of BMP-3b and cerberus is required for head formation of Xenopus embryos. Dev. Biol. 2003;260: 138–57.

25.  Dohrmann, C.E., Hemmati-Brivanlou, A., Thomsen, G.H., Fields, A., Woolf, T.M., Melton, D.A. Expression of activin mRNA during early development in Xenopus laevis. Dev. Biol. 1993; 157: 474–83.

26.  Khokha, M.K., Yeh, J., Grammer, T.C., Harland, R.M. Depletion of three BMP antagonists from Spemann’s organizer leads to a catastrophic loss of dorsal structures. Dev. Cell 2005;8: 401–11.

27.  Massagué J and Wotton D. Transcriptional control by the TGF‐β/Smad signaling system. EMBO J 2000; 19: 1745–54

28.  Miyazawa, K., Shinozaki, M., Hara, T., Furuya, T., Miyazono, K. Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells 2002;7: 1191–1204.

29.  Daluiski A, Engstrand T, Bahamonde ME, Gamer LW, Agius E, Stevenson SL et al. Bone morphogenetic protein-3 is a negative regulator of bone density. Nature genetics. 2001 Jan 1;27(1):84-8.

30.  Faucheux, C., Ulysse, F., Bareille, R., Reddi, A.H., Amedee, J. Opposing actions of BMP3 and TGF beta 1 in human bone marrow stromal cell growth and differentiation. Biochem. Biophys. Res. Commun. 1997; 241: 787–93.

31.  Niveditha, Srikanth, Singh H., Srinivasa R. A Prospective Case-Control Study to Evaluate the Effect of Chronic Anti-epileptic therapy on Bone Turnover Markers. Research J. Pharm. and Tech. 6(12): Dec. 2013; Page 1321-1324.

32.  Fatima Malik Abood1, Ghassan A. Abbas HD. Conserv, Luma Jasim Witwit, Nada Khazal Kadhim Hindi, Halah Khaleel Ahmed Abu Khmra, Mohmmed R. Abid Ali. The occurrence of alveolar bone resorption with oral bacterial infection. Research J. Pharm. and Tech. 2017; 10(6): 1997-2000.

33.  Subashree R., Radhika Arjunkumar. Vitamin D Deficiency in Periodontal Health. Research J. Pharm. and Tech. 7(2): Feb. 2014; Page 248-252.

34.  Lebrun JJ, Takabe K, Chen Y and Vale W. Roles of pathway‐specific and inhibitory Smads in activin receptor signaling. Mol Endocrinol. 1999; 13: 15–23

35.  Kretzschmar M, Doody J and Massagué J. Opposing BMP and EGF signalling pathways converge on the TGF‐β family mediator Smad1. Nature. 1997; 389: 618–22.

36.  Miyazono, K. Positive and negative regulation of TGF‐β signaling. J Cell Sci, 2000; 113:1101–09.

37.  Hiraki Y, Inoue H, Shigeno C, Sanma Y, Bentz H, Rosen DM. et al. Bone morphogenetic proteins (BMP‐2 and BMP‐3) promote growth and expression of the differentiated phenotype of rabbit chondrocytes and osteoblastic MC3T3‐E1 cells in vitro. Journal of Bone and Mineral Research. 1991 Dec 1;6(12):1373-85.

38.  Radhakrishna B, Ashok M, Harish PL, Veera Jyothsna M, Shivalinge Gowda KP. Current and Future Trends of Drugs Used in Osteoporosis. Research J. Pharmacology and Pharmacodynamics. 2011; 3(6): 329-333.

 

 

Received on 26.11.2017            Modified on 18.12.2017

Accepted on 20.02.2018         © RJPT All right reserved