Bone morphogenetic protein 7

Bone morphogenetic protein 7 or BMP7 (also known as osteogenic protein-1 or OP-1) is a protein that in humans is encoded by the BMP7 gene.[1]

Function

The protein encoded by this gene is a member of the TGF-β superfamily. Like other members of the bone morphogenetic protein family of proteins, it plays a key role in the transformation of mesenchymal cells into bone and cartilage. It is inhibited by noggin and a similar protein, chordin, which are expressed in the Spemann-Mangold Organizer. BMP7 may be involved in bone homeostasis. It is expressed in the brain, kidneys and bladder.[2]

BMP7 induces the phosphorylation of SMAD1 and SMAD5, which in turn induce transcription of numerous osteogenic genes.[3] It has been demonstrated that BMP7 treatment is sufficient to induce all of the genetic markers of osteoblast differentiation in many cell types.[2]

Role in vertebrate development

The role of BMP7 in mammalian kidney development is through induction of MET of the metanephrogenic blastema.[4] The epithelial tissue emerging from this MET process eventually forms the tubules and glomeruli of the nephron.[4] BMP-7 is also important in homeostasis of the adult kidney by inhibiting ephithelial-mesenchymal transition (EMT). BMP-7 expression is attenuated when the nephron is placed under inflammatory or ischemic stress, leading to EMT, which can result in fibrosis of the kidney.[5] This type of fibrosis often leads to renal failure, and is predictive of end stage renal disease.[6]

BMP7 has been discovered to be crucial in the determination of ventral-dorsal organization in zebrafish. BMP7 causes the expression of ventral phenotypes while its complete inhibition creates a dorsal phenotype. Moreover, BMP7 is eventually partially "turned off" in embryonic development in order to create the dorsal parts of the organism.[7]

In many early developmental experiments using zebrafish, scientists used caBMPR (constitutively active) and tBMP (truncated receptor) to determine the effect of BMP7 in embryogensis. They found that the constitutively active, which causes BMP to be expressed everywhere creates a ventralized phenotype, whereas truncated, dorsalized.

Therapeutic application

Human recombinant BMP7 has surgical uses and is marketed under the brand name OP1 (sold by Olympus, who bought it from Stryker). It can be used to aid in the fusion of vertebral bodies to prevent neurologic trauma.[8] Also in the treatment of tibial non-union, frequently in cases where a bone graft has failed.[9] rhBMP-2 is much more widely used clinically because it helps grow bone better than rhBMP-7 and other BMPs.[10]

BMP7 also has the potential for treatment of chronic kidney disease.[11][12] Kidney disease is characterized by derangement of the tubular architecture by both myofibroblast buildup and monocyte infiltration [13] Because endogenous BMP-7 is an inhibitor of the TGF-β signaling cascade that induces fibrosis, the use of exogenous recombinant BMP-7 (rhBMP-7) could be a viable treatment of chronic kidney disease.[4] It is also thought that BMP-7 reverses fibrosis and EMT through reduction in monocyte infiltration into inflamed tissue.[11] On a molecular level, BMP-7 represses inflammation by knocking down the expression of several pro-inflammatory cytokines produced by monocytes.[11] Reducing this inflammatory stress, in turn, reduces the chance of fibrosis.[5]

Regardless of the mechanism of fibrosis or the origin of myofibroblasts, exogenous BMP-7 has been shown to reverse the EMT process and trigger MET.[4] Eventually this restores the healthy epithelial cell population, and normal function of the kidneys in mice.[4] This is pertinent in humans as well, because many diseases stemming from organ fibrosis occur via the EMT process.[5] The epithelial-menenchymal transition is also problematic in cancer metastasis, so the diminution of EMT with recombinant DNA could have great implications in future cancer treatment options.[5]

BMP7 administration has been proposed as a possible treatment for human infertility due to poor response to FSH treatment.[14]

Promotion of brown fat

It was discovered that mice injected with BMP7 increased their production of "good" brown fat cells, while keeping their levels of the normal white fat cells constant. A BMP7 therapy for obesity in humans may be developed as a result.[15][16]

References

  1. ↑ Hahn GV, Cohen RB, Wozney JM, Levitz CL, Shore EM, Zasloff MA, Kaplan FS (November 1992). "A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7". Genomics 14 (3): 759–62. doi:10.1016/S0888-7543(05)80181-8. PMID 1427904.
  2. 1 2 Chen D, Zhao M, Mundy GR (December 2004). "Bone morphogenetic proteins". Growth Factors 22 (4): 233–41. doi:10.1080/08977190412331279890. PMID 15621726.
  3. ↑ Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (August 2001). "Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads". EMBO J. 20 (15): 4132–42. doi:10.1093/emboj/20.15.4132. PMC 149146. PMID 11483516.
  4. 1 2 3 4 5 Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Müller GA, Kalluri R (2003). "Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models". Am. J. Physiol. Renal Physiol. 285 (6): F1060–7. doi:10.1152/ajprenal.00191.2002. PMID 12915382.
  5. 1 2 3 4 Kalluri R, Weinberg RA (2009). "The basics of epithelial-mesenchymal transition". J. Clin. Invest. 119 (6): 1420–8. doi:10.1172/JCI39104. PMC 2689101. PMID 19487818.
  6. ↑ Wang SN, Lapage J, Hirschberg R (2001). "Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy". J. Am. Soc. Nephrol. 12 (11): 2392–9. PMID 11675415.
  7. ↑ Myers DC, Sepich DS, Solnica-Krezel L (March 2002). "Bmp activity gradient regulates convergent extension during zebrafish gastrulation". Dev. Biol. 243 (1): 81–98. doi:10.1006/dbio.2001.0523. PMID 11846479.
  8. ↑ Vaccaro AR, Whang PG, Patel T, Phillips FM, Anderson DG, Albert TJ, Hilibrand AS, Brower RS, Kurd MF, Appannagari A, Patel M, Fischgrund JS (2008). "The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study". Spine J 8 (3): 457–65. doi:10.1016/j.spinee.2007.03.012. PMID 17588821.
  9. ↑ Zimmermann G, Müller U, Löffler C, Wentzensen A, Moghaddam A (November 2007). "[Therapeutic outcome in tibial pseudarthrosis: bone morphogenetic protein 7 (BMP-7) versus autologous bone grafting for tibial fractures]". Unfallchirurg (in German) 110 (11): 931–8. doi:10.1007/s00113-007-1347-y. PMID 17989951.
  10. ↑ Even J, Eskander M, Kang J (2012). "Bone morphogenetic protein in spine surgery: current and future uses". J Am Acad Orthop Surg 20 (9): 547–52. doi:10.5435/JAAOS-20-09-547. PMID 22941797.
  11. 1 2 3 Gould SE, Day M, Jones SS, Dorai H (2002). "BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells". Kidney Int. 61 (1): 51–60. doi:10.1046/j.1523-1755.2002.00103.x. PMID 11786084.
  12. ↑ González EA, Lund RJ, Martin KJ, McCartney JE, Tondravi MM, Sampath TK, Hruska KA (April 2002). "Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7". Kidney Int. 61 (4): 1322–31. doi:10.1046/j.1523-1755.2002.00258.x. PMID 11918739.
  13. ↑ Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S (2002). "Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function". J. Am. Soc. Nephrol. 13 Suppl 1: S14–21. PMID 11792757.
  14. ↑ Shi J, Yoshino O, Osuga Y, Nishii O, Yano T, Taketani Y (March 2010). "Bone morphogenetic protein 7 (BMP-7) increases the expression of follicle-stimulating hormone (FSH) receptor in human granulosa cells". Fertil. Steril. 93 (4): 1273–9. doi:10.1016/j.fertnstert.2008.11.014. PMID 19108831.
  15. ↑ Jha A (2008-08-21). "Obesity: Scientists identify protein that promotes fat-burning". Science. guardian.co.uk. Retrieved 2008-09-03.
  16. ↑ Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR (August 2008). "New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure". Nature 454 (7207): 1000–4. doi:10.1038/nature07221. PMC 2745972. PMID 18719589.

Further reading

External links

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