The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing

Abstract

Purpose

The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.

Methods

Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.

Results

Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.

Conclusions

Current issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.

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References

  1. 1.

    The American College of Surgeons (2002) National trauma data bank report. The American College of Surgeons, Chicago, IL

  2. 2.

    Deutsche Bank Alex Brown (2001) Estimates and company information. Deutsche Bank AG, Frankfurt am Main

  3. 3.

    American Academy of Orthopaedic Surgeons (2000) Musculoskeletal injuries report: incidence, risk factors and prevention. AAOS

  4. 4.

    Giannoudis PV, Kanakaris NK, Einhorn TA (2007) Interaction of bone morphogenetic proteins with cells of the osteoclast lineage: review of the existing evidence. Osteoporos Int 18:1565–1581

    CAS  PubMed  Google Scholar 

  5. 5.

    Pecina M, Vukicevic S (2007) Biological aspects of bone, cartilage and tendon regeneration. Int Orthop 31:719–720

    PubMed Central  PubMed  Google Scholar 

  6. 6.

    Parfitt AM (1982) The coupling of bone formation to bone resorption: a critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis. Metab Bone Dis Relat Res 4:1–6

    CAS  PubMed  Google Scholar 

  7. 7.

    Lacey DL, Timms E, Tan HL et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176

    CAS  PubMed  Google Scholar 

  8. 8.

    Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342

    CAS  PubMed  Google Scholar 

  9. 9.

    Borovecki F, Pecina-Slaus N, Vukicevic S (2007) Biological mechanisms of bone and cartilage remodelling–genomic perspective. Int Orthop 31:799–805

    CAS  PubMed Central  PubMed  Google Scholar 

  10. 10.

    Sanchez-Fernandez MA, Gallois A, Riedl T, Jurdic P, Hoflack B (2008) Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling. PLoS One 3:e3537

    PubMed Central  PubMed  Google Scholar 

  11. 11.

    Kubota K, Sakikawa C, Katsumata M, Nakamura T, Wakabayashi K (2002) PDGF BB purified from osteoclasts acts as osteoblastogenesis inhibitory factor (OBIF). J Biomol Tech 13:62–71

    PubMed Central  PubMed  Google Scholar 

  12. 12.

    Vukicevic S, Luyten FP, Kleinman HK, Reddi AH (1990) Differentiation of canalicular cell processes in bone cells by basement membrane matrix components: regulation by discrete domains of laminin. Cell 63:437–445

    CAS  PubMed  Google Scholar 

  13. 13.

    Grasser WA, Orlic I, Borovecki F, Riccardi KA, Simic P, Vukicevic S, Paralkar VM (2007) BMP-6 exerts its osteoinductive effect through activation of IGF-I and EGF pathways. Int Orthop 31:759–765

    CAS  PubMed Central  PubMed  Google Scholar 

  14. 14.

    Mundy GR (1991) The effects of TGF-beta on bone. Ciba Found Symp 157:137–143

    CAS  PubMed  Google Scholar 

  15. 15.

    Arai S, Amizuka N, Azuma Y, Takeshita S, Kudo A (2003) Osteoclastogenesis-related antigen, a novel molecule on mouse stromal cells, regulates osteoclastogenesis. J Bone Miner Res 18:686–695

    CAS  PubMed  Google Scholar 

  16. 16.

    Chang SC, Hoang B, Thomas JT, Vukicevic S, Luyten FP, Ryba NJ, Kozak CA, Reddi AH, Moos M Jr (1994) Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development. J Biol Chem 269:28227–28234

    CAS  PubMed  Google Scholar 

  17. 17.

    Ozkaynak E, Rueger DC, Drier EA, Corbett C, Ridge RJ, Sampath TK, Oppermann H (1990) OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO J 9:2085–2093

    CAS  PubMed Central  PubMed  Google Scholar 

  18. 18.

    Sampath TK, Reddi AH (1981) Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc Natl Acad Sci USA 78:7599–7603

    CAS  PubMed Central  PubMed  Google Scholar 

  19. 19.

    ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin CH, Miyazono K (1994) Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269:16985–16988

    PubMed  Google Scholar 

  20. 20.

    Urist MR (1965) Bone: formation by autoinduction. Science 150:893–899

    CAS  PubMed  Google Scholar 

  21. 21.

    Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA (1988) Novel regulators of bone formation: molecular clones and activities. Science 242:1528–1534

    CAS  PubMed  Google Scholar 

  22. 22.

    Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S, Ke HZ, Qi H, Owen TA, Thompson DD (1998) Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J Biol Chem 273:13760–13767

    CAS  PubMed  Google Scholar 

  23. 23.

    Vukicevic S, Stavljenic A, Pecina M (1995) Discovery and clinical applications of bone morphogenetic proteins. Eur J Clin Chem Clin Biochem 33:661–671

    CAS  PubMed  Google Scholar 

  24. 24.

    Vukicevic S, Luyten FP, Reddi AH (1989) Stimulation of the expression of osteogenic and chondrogenic phenotypes in vitro by osteogenin. Proc Natl Acad Sci USA 86:8793–8797

    CAS  PubMed Central  PubMed  Google Scholar 

  25. 25.

    Lissenberg-Thunnissen SN, de Gorter DJ, Sier CF, Schipper IB (2011) Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop 35:1271–1280

    PubMed Central  PubMed  Google Scholar 

  26. 26.

    Graf D, Economides AN (2008) Dissection of bone morphogenetic protein signalling using genome engineering tools. In: Vukicevic S, Sampath TK (eds) Bone Morphogenetic Proteins: From Local to Systemic Therapeutics. Birkhauser Verlag, Basel, pp 115–140

    Google Scholar 

  27. 27.

    Aspenberg P, Basic N, Tagil M, Vukicevic S (2000) Reduced expression of BMP-3 due to mechanical loading: a link between mechanical stimuli and tissue differentiation. Acta Orthop Scand 71:558–562

    CAS  PubMed  Google Scholar 

  28. 28.

    Sieber C, Schwaerzer GK, Knaus P (2008) Bone morphogenetic protein signalling is fine-tuned on multiple levels. In: Vukicevic S, Sampath TK (eds) Bone Morphogenetic Proteins: From Local to Systemic Therapeutics. Birkhauser Verlag, Basel, pp 81–114

    Google Scholar 

  29. 29.

    Anticevic D, Jelic M, Vukicevic S (2006) Treatment of a congenital pseudarthrosis of the tibia by osteogenic protein-1 (bone morphogenetic protein-7): a case report. J Pediatr Orthop B 15:220–221

    PubMed  Google Scholar 

  30. 30.

    Bilic R, Simic P, Jelic M, Stern-Padovan R, Dodig D, van Meerdervoort HP, Martinovic S, Ivankovic D, Pecina M, Vukicevic S (2006) Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis. Int Orthop 30:128–134

    CAS  PubMed Central  PubMed  Google Scholar 

  31. 31.

    Dorai H, Vukicevic S, Sampath TK (2000) Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro. J Cell Physiol 184:37–45

    CAS  PubMed  Google Scholar 

  32. 32.

    Grgic M, Jelic M, Basic V, Basic N, Pecina M, Vukicevic S (1997) Regeneration of articular cartilage defects in rabbits by osteogenic protein-1 (bone morphogenetic protein-7). Acta Med Croatica 51:23–27

    CAS  PubMed  Google Scholar 

  33. 33.

    Jelic M, Pecina M, Haspl M, Kos J, Taylor K, Maticic D, McCartney J, Yin S, Rueger D, Vukicevic S (2001) Regeneration of articular cartilage chondral defects by osteogenic protein-1 (bone morphogenetic protein-7) in sheep. Growth Factors 19:101–113

    CAS  PubMed  Google Scholar 

  34. 34.

    Mihelic R, Pecina M, Jelic M, Zoricic S, Kusec V, Simic P, Bobinac D, Lah B, Legovic D, Vukicevic S (2004) Bone morphogenetic protein-7 (osteogenic protein-1) promotes tendon graft integration in anterior cruciate ligament reconstruction in sheep. Am J Sports Med 32:1619–1625

    PubMed  Google Scholar 

  35. 35.

    de Gorter DJ, Krause C, Lowik CWGM, Bezooijen RL, ten Dijke P (2008) Control of bone mass by sclerostin: Inhibiting BMP- and WNT-induced bone formation. In: Vukicevic S, Sampath TK (eds) Bone Morphogenetic Proteins: From Local to Systemic Therapeutics. Birkhauser Verlag, Basel, pp 257–276

    Google Scholar 

  36. 36.

    Vukicevic S, Kopp JB, Luyten FP, Sampath TK (1996) Induction of nephrogenic mesenchyme by osteogenic protein 1 (bone morphogenetic protein 7). Proc Natl Acad Sci USA 93:9021–9026

    CAS  PubMed Central  PubMed  Google Scholar 

  37. 37.

    Katagiri T, Boorla S, Frendo JL, Hogan BL, Karsenty G (1998) Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice. Dev Genet 22:340–348

    CAS  PubMed  Google Scholar 

  38. 38.

    Friedlander C, Nerubay J, Katznelson A, Nebel L (1979) Osteogenesis by periosteal transplant. Experimental study of spinal fusion in rats. Isr J Med Sci 15:38–42

    CAS  PubMed  Google Scholar 

  39. 39.

    Helder MN, Ozkaynak E, Sampath KT, Luyten FP, Latin V, Oppermann H, Vukicevic S (1995) Expression pattern of osteogenic protein-1 (bone morphogenetic protein-7) in human and mouse development. J Histochem Cytochem 43:1035–1044

    CAS  PubMed  Google Scholar 

  40. 40.

    Helder MN, Karg H, Bervoets TJ, Vukicevic S, Burger EH, D'Souza RN, Woltgens JH, Karsenty G, Bronckers AL (1998) Bone morphogenetic protein-7 (osteogenic protein-1, OP-1) and tooth development. J Dent Res 77:545–554

    CAS  PubMed  Google Scholar 

  41. 41.

    Pecina M, Giltaij LR, Vukicevic S (2001) Orthopaedic applications of osteogenic protein-1 (BMP-7). Int Orthop 25:203–208

    CAS  PubMed Central  PubMed  Google Scholar 

  42. 42.

    Pecina M, Haspl M, Jelic M, Vukicevic S (2003) Repair of a resistant tibial non-union with a recombinant bone morphogenetic protein-7 (rhBMP-7). Int Orthop 27:320–321

    CAS  PubMed Central  PubMed  Google Scholar 

  43. 43.

    Perry MJ, McDougall KE, Hou SC, Tobias JH (2008) Impaired growth plate function in bmp-6 null mice. Bone 42:216–225

    CAS  PubMed  Google Scholar 

  44. 44.

    Ripamonti U, Vukicevic S (1995) Bone morphogenetic proteins: from developmental biology to molecular therapeutics. S Afr J Sci 91:277–280

    Google Scholar 

  45. 45.

    Simic P, Vukicevic S (2007) Bone morphogenetic proteins: from developmental signals to tissue regeneration. Conference on bone morphogenetic proteins. EMBO Rep 8:327–331

    CAS  PubMed Central  PubMed  Google Scholar 

  46. 46.

    ten Dijke P (2006) Bone morphogenetic protein signal transduction in bone. Curr Med Res Opin 22(Suppl 1):S7–S11

    PubMed  Google Scholar 

  47. 47.

    Vukicevic S, Sampath TK (2002) Bone Morphogenetic Proteins: From Laboratory to Clinical Practice. Birkhauser Verlag, Basel

    Google Scholar 

  48. 48.

    Vukicevic S, Grgurevic L (2009) BMP-6 and mesenchymal stem cell differentiation. Cytokine Growth Factor Rev 20:441–448

    CAS  PubMed  Google Scholar 

  49. 49.

    Simic P, Vukicevic S (2004) BMPs in development. In: Vukicevic S, Pecina M (eds) Bone Morphogenetic Proteins: Regeneration of Bone and Beyond. Birkhauser Verlag, Basel, pp 73–108

    Google Scholar 

  50. 50.

    Bishop GB, Einhorn TA (2007) Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop 31:721–727

    PubMed Central  PubMed  Google Scholar 

  51. 51.

    White AP, Vaccaro AR, Hall JA, Whang PG, Friel BC, McKee MD (2007) Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion. Int Orthop 31:735–741

    PubMed Central  PubMed  Google Scholar 

  52. 52.

    Govender S, Csimma C, Genant HK et al (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 84-A:2123–2134

    PubMed  Google Scholar 

  53. 53.

    Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA (2002) Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine 27:2396–2408, Phila Pa 1976

    PubMed  Google Scholar 

  54. 54.

    Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A(Suppl 1):S151–S158

    PubMed  Google Scholar 

  55. 55.

    Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, Helfand M (2013) Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med 158:890–902

    PubMed  Google Scholar 

  56. 56.

    Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, Stewart LA (2013) Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med 158:877–889

    PubMed  Google Scholar 

  57. 57.

    Axelrad TW, Steen B, Lowenberg DW, Creevy WR, Einhorn TA (2008) Heterotopic ossification after the use of commercially available recombinant human bone morphogenetic proteins in four patients. J Bone Joint Surg Br 90:1617–1622

    CAS  PubMed  Google Scholar 

  58. 58.

    Boden SD, Zdeblick TA, Sandhu HS, Heim SE (2000) The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine 25:376–381, Phila Pa 1976

    CAS  PubMed  Google Scholar 

  59. 59.

    Carragee EJ, Mitsunaga KA, Hurwitz EL, Scuderi GJ (2011) Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. Spine J 11:511–516

    PubMed  Google Scholar 

  60. 60.

    Hiremath GK, Steinmetz MP, Krishnaney AA (2009) Is it safe to use recombinant human bone morphogenetic protein in posterior cervical fusion? Spine 34:885–889, Phila Pa 1976

    PubMed  Google Scholar 

  61. 61.

    Kang JD (2011) Another complication associated with rhBMP-2? Spine J 11:517–519

    PubMed  Google Scholar 

  62. 62.

    Kleeman TJ, Ahn UM, Talbot-Kleeman A (2001) Laparoscopic anterior lumbar interbody fusion with rhBMP-2: a prospective study of clinical and radiographic outcomes. Spine 26:2751–2756, Phila Pa 1976

    CAS  PubMed  Google Scholar 

  63. 63.

    Mroz TE, Wang JC, Hashimoto R, Norvell DC (2010) Complications related to osteobiologics use in spine surgery: a systematic review. Spine 35:S86–S104, Phila Pa 1976

    PubMed  Google Scholar 

  64. 64.

    Chatzinikolaidou M, Lichtinger TK, Muller RT, Jennissen HP (2010) Peri-implant reactivity and osteoinductive potential of immobilized rhBMP-2 on titanium carriers. Acta Biomater 6:4405–4421

    CAS  PubMed  Google Scholar 

  65. 65.

    Ekrol I, Hajducka C, Court-Brown C, McQueen MM (2008) A comparison of rhBMP-7 (OP-1) and autogenous graft for metaphyseal defects after osteotomy of the distal radius. Injury 39(Suppl 2):S73–S82

    PubMed  Google Scholar 

  66. 66.

    McGee MA, Findlay DM, Howie DW, Carbone A, Ward P, Stamenkov R, Page TT, Bruce WJ, Wildenauer CI, Toth C (2004) The use of OP-1 in femoral impaction grafting in a sheep model. J Orthop Res 22:1008–1015

    CAS  PubMed  Google Scholar 

  67. 67.

    Notices from European Union Institutions Bodies Offices and Agencies (2011) Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMA/410/01 rev.3). Official Journal of the European Union (2011/C 73/01)

  68. 68.

    Lieberman JR, Daluiski A, Einhorn TA (2002) The role of growth factors in the repair of bone. Biology and clinical applications. J Bone Joint Surg Am 84-A:1032–1044

    PubMed  Google Scholar 

  69. 69.

    Reddi AH, Huggins C (1972) Biochemical sequences in the transformation of normal fibroblasts in adolescent rats. Proc Natl Acad Sci USA 69:1601–1605

    CAS  PubMed Central  PubMed  Google Scholar 

  70. 70.

    Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S (2005) Circulating osteoblast-lineage cells in humans. N Engl J Med 352:1959–1966

    CAS  PubMed  Google Scholar 

  71. 71.

    Vukicevic S, Luyten FP, Reddi AH (1990) Osteogenin inhibits proliferation and stimulates differentiation in mouse osteoblast-like cells (MC3T3-E1). Biochem Biophys Res Commun 166:750–756

    CAS  PubMed  Google Scholar 

  72. 72.

    Kamiya N, Ye L, Kobayashi T, Lucas DJ, Mochida Y, Yamauchi M, Kronenberg HM, Feng JQ, Mishina Y (2008) Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. J Bone Miner Res 23:2007–2017

    CAS  PubMed Central  PubMed  Google Scholar 

  73. 73.

    Okamoto M, Murai J, Imai Y, Ikegami D, Kamiya N, Kato S, Mishina Y, Yoshikawa H, Tsumaki N (2011) Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice. J Bone Miner Res 26:2511–2522

    CAS  PubMed  Google Scholar 

  74. 74.

    Okamoto M, Murai J, Yoshikawa H, Tsumaki N (2006) Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res 21:1022–1033

    CAS  PubMed  Google Scholar 

  75. 75.

    Minear S, Leucht P, Miller S, Helms JA (2010) rBMP represses Wnt signaling and influences skeletal progenitor cell fate specification during bone repair. J Bone Miner Res 25:1196–1207

    CAS  PubMed Central  PubMed  Google Scholar 

  76. 76.

    Kamiya N, Kobayashi T, Mochida Y, Yu PB, Yamauchi M, Kronenberg HM, Mishina Y (2010) Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. J Bone Miner Res 25:200–210

    CAS  PubMed Central  PubMed  Google Scholar 

  77. 77.

    Kaneko H, Arakawa T, Mano H, Kaneda T, Ogasawara A, Nakagawa M, Toyama Y, Yabe Y, Kumegawa M, Hakeda Y (2000) Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. Bone 27:479–486

    CAS  PubMed  Google Scholar 

  78. 78.

    Otsuka E, Notoya M, Hagiwara H (2003) Treatment of myoblastic C2C12 cells with BMP-2 stimulates vitamin D-induced formation of osteoclasts. Calcif Tissue Int 73:72–77

    CAS  PubMed  Google Scholar 

  79. 79.

    Onishi T, Ishidou Y, Nagamine T, Yone K, Imamura T, Kato M, Sampath TK, ten Dijke P, Sakou T (1998) Distinct and overlapping patterns of localization of bone morphogenetic protein (BMP) family members and a BMP type II receptor during fracture healing in rats. Bone 22:605–612

    CAS  PubMed  Google Scholar 

  80. 80.

    Garimella R, Tague SE, Zhang J, Belibi F, Nahar N, Sun BH, Insogna K, Wang J, Anderson HC (2008) Expression and synthesis of bone morphogenetic proteins by osteoclasts: a possible path to anabolic bone remodeling. J Histochem Cytochem 56:569–577

    CAS  PubMed Central  PubMed  Google Scholar 

  81. 81.

    Anderson HC, Hodges PT, Aguilera XM, Missana L, Moylan PE (2000) Bone morphogenetic protein (BMP) localization in developing human and rat growth plate, metaphysis, epiphysis, and articular cartilage. J Histochem Cytochem 48:1493–1502

    CAS  PubMed  Google Scholar 

  82. 82.

    Nishimura T, Simmons DJ, Mainous EG (1997) The origin of bone formed by heterotopic periosteal autografts. J Oral Maxillofac Surg 55:1265–1268

    CAS  PubMed  Google Scholar 

  83. 83.

    Little DG, McDonald M, Bransford R, Godfrey CB, Amanat N (2005) Manipulation of the anabolic and catabolic responses with OP-1 and zoledronic acid in a rat critical defect model. J Bone Miner Res 20:2044–2052

    CAS  PubMed  Google Scholar 

  84. 84.

    Cowan CM, Aalami OO, Shi YY, Chou YF, Mari C, Thomas R, Quarto N, Nacamuli RP, Contag CH, Wu B, Longaker MT (2005) Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover. Tissue Eng 11:645–658

    CAS  PubMed  Google Scholar 

  85. 85.

    Jeppsson C, Astrand J, Tagil M, Aspenberg P (2003) A combination of bisphosphonate and BMP additives in impacted bone allografts. Acta Orthop Scand 74:483–489

    PubMed  Google Scholar 

  86. 86.

    Miyaji H, Sugaya T, Kato K, Kawamura N, Tsuji H, Kawanami M (2006) Dentin resorption and cementum-like tissue formation by bone morphogenetic protein application. J Periodontal Res 41:311–315

    CAS  PubMed  Google Scholar 

  87. 87.

    Cunningham NS, Paralkar V, Reddi AH (1992) Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor beta 1 mRNA expression. Proc Natl Acad Sci USA 89:11740–11744

    CAS  PubMed Central  PubMed  Google Scholar 

  88. 88.

    Hentunen TA, Cunningham NS, Vuolteenaho O, Reddi AH, Vaananen HK (1994) Osteoclast recruiting activity in bone matrix. Bone Miner 25:183–198

    CAS  PubMed  Google Scholar 

  89. 89.

    Hentunen TA, Lakkakorpi PT, Tuukkanen J, Lehenkari PP, Sampath TK, Vaananen HK (1995) Effects of recombinant human osteogenic protein-1 on the differentiation of osteoclast-like cells and bone resorption. Biochem Biophys Res Commun 209:433–443

    CAS  PubMed  Google Scholar 

  90. 90.

    Kanatani M, Sugimoto T, Kaji H, Kobayashi T, Nishiyama K, Fukase M, Kumegawa M, Chihara K (1995) Stimulatory effect of bone morphogenetic protein-2 on osteoclast-like cell formation and bone-resorbing activity. J Bone Miner Res 10:1681–1690

    CAS  PubMed  Google Scholar 

  91. 91.

    Hofbauer LC, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1998) Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic protein-2, and cytokines. Biochem Biophys Res Commun 250:776–781

    CAS  PubMed  Google Scholar 

  92. 92.

    Koide M, Murase Y, Yamato K, Noguchi T, Okahashi N, Nishihara T (1999) Bone morphogenetic protein-2 enhances osteoclast formation mediated by interleukin-1 alpha through upregulation of osteoclast differentiation factor and cyclooxygenase-2. Biochem Biophys Res Commun 259:97–102

    CAS  PubMed  Google Scholar 

  93. 93.

    Abe E, Yamamoto M, Taguchi Y, Lecka-Czernik B, O'Brien CA, Economides AN, Stahl N, Jilka RL, Manolagas SC (2000) Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice: antagonism by noggin. J Bone Miner Res 15:663–673

    CAS  PubMed  Google Scholar 

  94. 94.

    Koseki T, Gao Y, Okahashi N, Murase Y, Tsujisawa T, Sato T, Yamato K, Nishihara T (2002) Role of TGF-beta family in osteoclastogenesis induced by RANKL. Cell Signal 14:31–36

    CAS  PubMed  Google Scholar 

  95. 95.

    Dumic-Cule I, Grcevic D, Draca N, Tikvica A, Rogic D, Grgurevic L, Vukicevic S (2013) Effect of BMP2, BMP6 and BMP7 on bone in rats with removed thyroid and parathyroid glands. Int Orthop, in press

  96. 96.

    Wutzl A, Brozek W, Lernbass I, Rauner M, Hofbauer G, Schopper C, Watzinger F, Peterlik M, Pietschmann P (2006) Bone morphogenetic proteins 5 and 6 stimulate osteoclast generation. J Biomed Mater Res A 77:75–83

    PubMed  Google Scholar 

  97. 97.

    Ghosh-Choudhury N, Singha PK, Woodruff K, St Clair P, Bsoul S, Werner SL, Choudhury GG (2006) Concerted action of Smad and CREB-binding protein regulates bone morphogenetic protein-2-stimulated osteoblastic colony-stimulating factor-1 expression. J Biol Chem 281:20160–20170

    CAS  PubMed  Google Scholar 

  98. 98.

    Ripamonti U, Heliotis M, Ferretti C (2007) Bone morphogenetic proteins and the induction of bone formation: from laboratory to patients. Oral Maxillofac Surg Clin North Am 19:575–589

    PubMed  Google Scholar 

  99. 99.

    Cook SD (1999) Preclinical and clinical evaluation of osteogenic protein-1 (BMP-7) in bony sites. Orthopedics 22:669–671

    CAS  PubMed  Google Scholar 

  100. 100.

    Seeherman H, Wozney JM (2005) Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev 16:329–345

    CAS  PubMed  Google Scholar 

  101. 101.

    Cook SD, Rueger DC (2002) Preclinical models of recombinant BMP induced healing of orthopedic defects. In: Vukicevic S, Sampath TK (eds) Bone Morphogenetic Proteins From Laboratory to Clinical Practice. Birkhauser Verlag, Basel, pp 121–144

    Google Scholar 

  102. 102.

    Blokhuis TJ, Patka P, Haarman HJTM, Giltaij LR (2002) Osteogenic protein-1 (OP-1, BMP-7) for stimulation of healing of closed fractures: Evidence based medicine and pre-clinical experience. In: Vukicevic S, Sampath TK (eds) Bone Morphogenetic Proteins From Laboratory to Clinical Practice. Birkhauser Verlag, Basel, pp 145–156

    Google Scholar 

  103. 103.

    Laursen M, Hoy K, Hansen ES, Gelineck J, Christensen FB, Bunger CE (1999) Recombinant bone morphogenetic protein-7 as an intracorporal bone growth stimulator in unstable thoracolumbar burst fractures in humans: preliminary results. Eur Spine J 8:485–490

    CAS  PubMed Central  PubMed  Google Scholar 

  104. 104.

    Hansen SM, Sasso RC (2006) Resorptive response of rhBMP2 simulating infection in an anterior lumbar interbody fusion with a femoral ring. J Spinal Disord Tech 19:130–134

    PubMed  Google Scholar 

  105. 105.

    Pradhan BB, Bae HW, Dawson EG, Patel VV, Delamarter RB (2006) Graft resorption with the use of bone morphogenetic protein: lessons from anterior lumbar interbody fusion using femoral ring allografts and recombinant human bone morphogenetic protein-2. Spine 31:E277–E284, Phila Pa 1976

    PubMed  Google Scholar 

  106. 106.

    Poynton AR, Lane JM (2002) Safety profile for the clinical use of bone morphogenetic proteins in the spine. Spine 27:S40–S48, Phila Pa 1976

    PubMed  Google Scholar 

  107. 107.

    Roberts SJ, Geris L, Kerckhofs G, Desmet E, Schrooten J, Luyten FP (2011) The combined bone forming capacity of human periosteal derived cells and calcium phosphates. Biomaterials 32:4393–4405

    CAS  PubMed  Google Scholar 

  108. 108.

    De Bari C, Dell'Accio F, Vanlauwe J, Eyckmans J, Khan IM, Archer CW, Jones EA, McGonagle D, Mitsiadis TA, Pitzalis C, Luyten FP (2006) Mesenchymal multipotency of adult human periosteal cells demonstrated by single-cell lineage analysis. Arthritis Rheum 54:1209–1221

    PubMed  Google Scholar 

  109. 109.

    Geesink RG, Hoefnagels NH, Bulstra SK (1999) Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. J Bone Joint Surg Br 81:710–718

    CAS  PubMed  Google Scholar 

  110. 110.

    Katagiri T, Imada M, Yanai T, Suda T, Takahashi N, Kamijo R (2002) Identification of a BMP-responsive element in Id1, the gene for inhibition of myogenesis. Genes Cells 7:949–960

    CAS  PubMed  Google Scholar 

  111. 111.

    Katagiri T, Akiyama S, Namiki M, Komaki M, Yamaguchi A, Rosen V, Wozney JM, Fujisawa-Sehara A, Suda T (1997) Bone morphogenetic protein-2 inhibits terminal differentiation of myogenic cells by suppressing the transcriptional activity of MyoD and myogenin. Exp Cell Res 230:342–351

    CAS  PubMed  Google Scholar 

  112. 112.

    Katagiri T, Yamaguchi A, Komaki M, Abe E, Takahashi N, Ikeda T, Rosen V, Wozney JM, Fujisawa-Sehara A, Suda T (1994) Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J Cell Biol 127:1755–1766

    CAS  PubMed  Google Scholar 

  113. 113.

    Nojima J, Kanomata K, Takada Y et al (2010) Dual roles of smad proteins in the conversion from myoblasts to osteoblastic cells by bone morphogenetic proteins. J Biol Chem 285:15577–15586

    CAS  PubMed Central  PubMed  Google Scholar 

  114. 114.

    Swiontkowski MF, Aro HT, Donell S, Esterhai JL, Goulet J, Jones A, Kregor PJ, Nordsletten L, Paiement G, Patel A (2006) Recombinant human bone morphogenetic protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am 88:1258–1265

    PubMed  Google Scholar 

  115. 115.

    Vukicevic S, Grgurevic L, Oppermann H (2012) Whole blood-derived coagulum device for treating bone defects. US 8197840

  116. 116.

    Bernardo ME, Emons JA, Karperien M, Nauta AJ, Willemze R, Roelofs H, Romeo S, Marchini A, Rappold GA, Vukicevic S, Locatelli F, Fibbe WE (2007) Hum.an mesenchymal stem cells derived from bone marrow display a better chondrogenic differentiation compared with other sources. Connect Tissue Res 48:132–140

    Google Scholar 

  117. 117.

    Sammons J, Ahmed N, El-Sheemy M, Hassan HT (2004) The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone development: effects on osteoblastic differentiation induced by parathyroid hormone and vitamin D(3). Stem Cells Dev 13:273–280

    CAS  PubMed  Google Scholar 

  118. 118.

    Martinovic S, Mazic S, Kisic V, Basic N, Jakic-Razumovic J, Borovecki F, Batinic D, Simic P, Grgurevic L, Labar B, Vukicevic S (2004) Expression of bone morphogenetic proteins in stromal cells from human bone marrow long-term culture. J Histochem Cytochem 52:1159–1167

    CAS  PubMed  Google Scholar 

  119. 119.

    Jung Y, Song J, Shiozawa Y, Wang J, Wang Z, Williams B, Havens A, Schneider A, Ge C, Franceschi RT, McCauley LK, Krebsbach PH, Taichman RS (2008) Hematopoietic stem cells regulate mesenchymal stromal cell induction into osteoblasts thereby participating in the formation of the stem cell niche. Stem Cells 26:2042–2051

    PubMed Central  PubMed  Google Scholar 

  120. 120.

    Martinovic S, Borovecki F, Miljavac V, Kisic V, Maticic D, Francetic I, Vukicevic S (2006) Requirement of a bone morphogenetic protein for the maintenance and stimulation of osteoblast differentiation. Arch Histol Cytol 69:23–36

    CAS  PubMed  Google Scholar 

  121. 121.

    Allendorph GP, Isaacs MJ, Kawakami Y, Izpisua Belmonte JC, Choe S (2007) BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors. Biochemistry 46:12238–12247

    CAS  PubMed  Google Scholar 

  122. 122.

    Korchynskyi O, van Bezooijen RL, Lowik CWGM, ten Dijke P (2004) Bone morphogenetic protein receptors and their nuclear effectors in bone formation. In: Vukicevic S, Sampath TK (eds) Bone morphogenetic proteins: Regeneration of bone and beyond. Birkauser Verlag AG, Basel, pp 9–114

    Google Scholar 

  123. 123.

    Song K, Krause C, Shi S, Patterson M, Suto R, Grgurevic L, Vukicevic S, van Dinther M, Falb D, ten Dijke P, Alaoui-Ismaili MH (2010) Identification of a key residue mediating bone morphogenetic protein (BMP)-6 resistance to noggin inhibition allows for engineered BMPs with superior agonist activity. J Biol Chem 285:12169–12180

    CAS  PubMed Central  PubMed  Google Scholar 

  124. 124.

    Vukicevic S, Sampath TK (2008) Bone morphogenetic proteins: from local to systemic therapeutics. Birkauser Verlag AG, Basel

    Google Scholar 

  125. 125.

    Zhang H, Bradley A (1996) Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122:2977–2986

    CAS  PubMed  Google Scholar 

  126. 126.

    Grgurevic L, Macek B, Erjavec I, Mann M, Vukicevic S (2007) Urine release of systemically administered bone morphogenetic protein hybrid molecule. J Nephrol 20:311–319

    CAS  PubMed  Google Scholar 

  127. 127.

    Grgurevic L, Macek B, Healy DR, Brault AL, Erjavec I, Cipcic A, Grgurevic I, Rogic D, Galesic K, Brkljacic J, Stern-Padovan R, Paralkar VM, Vukicevic S (2011) Circulating bone morphogenetic protein 1-3 isoform increases renal fibrosis. J Am Soc Nephrol 22:681–692

    CAS  PubMed Central  PubMed  Google Scholar 

  128. 128.

    Simic P, Culej JB, Orlic I, Grgurevic L, Draca N, Spaventi R, Vukicevic S (2006) Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption. J Biol Chem 281:25509–25521

    CAS  PubMed  Google Scholar 

  129. 129.

    Brkljacic J, Pauk M, Erjavec I, Cipcic A, Grgurevic L, Zadro R, Inman GJ, Vukicevic S (2013) Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity. Int Orthop 37:529–541

    PubMed  Google Scholar 

  130. 130.

    Cuellar A, Reddi AH (2013) Cell biology of osteochondromas: bone morphogenic protein signalling and heparan sulphates. Int Orthop 37:1591–1596

    PubMed  Google Scholar 

  131. 131.

    de Gorter DJ, van Dinther M, Korchynskyi O, ten Dijke P (2011) Biphasic effects of transforming growth factor beta on bone morphogenetic protein-induced osteoblast differentiation. J Bone Miner Res 26:1178–1187

    PubMed  Google Scholar 

  132. 132.

    Cook SD, Baffes GC, Wolfe MW, Sampath TK, Rueger DC (1994) Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clin Orthop Relat Res 302–312

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Acknowledgments

The research leading to these results has received funding from the European Community’s Seventh Framework Programme [FP7/2007-2013] under grant agreement n°HEALTH-F4-2011-279239.

We thank Durdica Car and Mirjana Marija Renic for providing animal care and experimentation in mice and rat studies.

Conflict of interest

HO, M. Jankolija, IP, M. Jurin and MK are employees of Genera Research.

SV is a founder and acts voluntarily as CEO of Genera Research.

DV, JC, JB, M. Pauk, IE, IF, IDC, M. Jelic, DD, TV, RN, VK, TBN, ZBT, JBS, SVT, M. Peric, M. Pecina and LG declare that they have no conflict of interest and certify that they have no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing, arrangements, etc.) that might pose a conflict of interest in connection with the submitted article.

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Correspondence to Slobodan Vukicevic.

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Mladenka Jurin contributed equally to this paper.

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Vukicevic, S., Oppermann, H., Verbanac, D. et al. The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing. International Orthopaedics (SICOT) 38, 635–647 (2014). https://doi.org/10.1007/s00264-013-2201-1

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Keywords

  • Bone regeneration
  • Bone morphogenetic protein 6 (BMP6)
  • Bone fracture
  • OSTEOGROW
  • Whole blood containing device
  • BMP2
  • BMP7
  • Commercial bone devices