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International Orthopaedics
Published in: International Orthopaedics 3/2014

01-03-2014 | Review Article

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

Authors: Slobodan Vukicevic, Hermann Oppermann, Donatella Verbanac, Morana Jankolija, Irena Popek, Jasna Curak, Jelena Brkljacic, Martina Pauk, Igor Erjavec, Igor Francetic, Ivo Dumic-Cule, Mislav Jelic, Dragan Durdevic, Tomislav Vlahovic, Ruder Novak, Vera Kufner, Tatjana Bordukalo Niksic, Marija Kozlovic, Zrinka Banic Tomisic, Jadranka Bubic-Spoljar, Ivancica Bastalic, Smiljka Vikic-Topic, Mihaela Peric, Marko Pecina, Lovorka Grgurevic

Published in: International Orthopaedics | Issue 3/2014

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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.
Literature
1.
The American College of Surgeons (2002) National trauma data bank report. The American College of Surgeons, Chicago, IL
2.
Deutsche Bank Alex Brown (2001) Estimates and company information. Deutsche Bank AG, Frankfurt am Main
3.
American Academy of Orthopaedic Surgeons (2000) Musculoskeletal injuries report: incidence, risk factors and prevention. AAOS
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 18:1565–1581PubMed
5.
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 4:1–6PubMed
7.
Lacey DL, Timms E, Tan HL et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176PubMed
8.
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342PubMed
9.
Borovecki F, Pecina-Slaus N, Vukicevic S (2007) Biological mechanisms of bone and cartilage remodelling–genomic perspective. Int Orthop 31:799–805PubMedCentralPubMed
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:e3537PubMedCentralPubMed
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 13:62–71PubMedCentralPubMed
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 63:437–445PubMed
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 31:759–765PubMedCentralPubMed
14.
Mundy GR (1991) The effects of TGF-beta on bone. Ciba Found Symp 157:137–143PubMed
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 18:686–695PubMed
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 269:28227–28234PubMed
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 9:2085–2093PubMedCentralPubMed
18.
Sampath TK, Reddi AH (1981) Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc Natl Acad Sci USA 78:7599–7603PubMedCentralPubMed
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 269:16985–16988PubMed
20.
Urist MR (1965) Bone: formation by autoinduction. Science 150:893–899PubMed
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 242:1528–1534PubMed
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 273:13760–13767PubMed
23.
Vukicevic S, Stavljenic A, Pecina M (1995) Discovery and clinical applications of bone morphogenetic proteins. Eur J Clin Chem Clin Biochem 33:661–671PubMed
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 86:8793–8797PubMedCentralPubMed
25.
Lissenberg-Thunnissen SN, de Gorter DJ, Sier CF, Schipper IB (2011) Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop 35:1271–1280PubMedCentralPubMed
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
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 71:558–562PubMed
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
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 15:220–221PubMed
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 30:128–134PubMedCentralPubMed
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 184:37–45PubMed
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 51:23–27PubMed
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 19:101–113PubMed
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 32:1619–1625PubMed
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
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 93:9021–9026PubMedCentralPubMed
37.
Katagiri T, Boorla S, Frendo JL, Hogan BL, Karsenty G (1998) Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice. Dev Genet 22:340–348PubMed
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 15:38–42PubMed
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 43:1035–1044PubMed
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 77:545–554PubMed
41.
Pecina M, Giltaij LR, Vukicevic S (2001) Orthopaedic applications of osteogenic protein-1 (BMP-7). Int Orthop 25:203–208PubMedCentralPubMed
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 27:320–321PubMedCentralPubMed
43.
Perry MJ, McDougall KE, Hou SC, Tobias JH (2008) Impaired growth plate function in bmp-6 null mice. Bone 42:216–225PubMed
44.
Ripamonti U, Vukicevic S (1995) Bone morphogenetic proteins: from developmental biology to molecular therapeutics. S Afr J Sci 91:277–280
45.
Simic P, Vukicevic S (2007) Bone morphogenetic proteins: from developmental signals to tissue regeneration. Conference on bone morphogenetic proteins. EMBO Rep 8:327–331PubMedCentralPubMed
46.
ten Dijke P (2006) Bone morphogenetic protein signal transduction in bone. Curr Med Res Opin 22(Suppl 1):S7–S11PubMed
47.
Vukicevic S, Sampath TK (2002) Bone Morphogenetic Proteins: From Laboratory to Clinical Practice. Birkhauser Verlag, Basel
48.
Vukicevic S, Grgurevic L (2009) BMP-6 and mesenchymal stem cell differentiation. Cytokine Growth Factor Rev 20:441–448PubMed
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
50.
Bishop GB, Einhorn TA (2007) Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop 31:721–727PubMedCentralPubMed
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 31:735–741PubMedCentralPubMed
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:2123–2134PubMed
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 1976PubMed
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–S158PubMed
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 158:890–902PubMed
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 158:877–889PubMed
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 90:1617–1622PubMed
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 1976PubMed
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 11:511–516PubMed
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 1976PubMed
61.
Kang JD (2011) Another complication associated with rhBMP-2? Spine J 11:517–519PubMed
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 1976PubMed
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 1976PubMed
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 6:4405–4421PubMed
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–S82PubMed
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 22:1008–1015PubMed
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.
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:1032–1044PubMed
69.
Reddi AH, Huggins C (1972) Biochemical sequences in the transformation of normal fibroblasts in adolescent rats. Proc Natl Acad Sci USA 69:1601–1605PubMedCentralPubMed
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 352:1959–1966PubMed
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 166:750–756PubMed
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 23:2007–2017PubMedCentralPubMed
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 26:2511–2522PubMed
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 21:1022–1033PubMed
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 25:1196–1207PubMedCentralPubMed
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 25:200–210PubMedCentralPubMed
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 27:479–486PubMed
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 73:72–77PubMed
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 22:605–612PubMed
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 56:569–577PubMedCentralPubMed
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 48:1493–1502PubMed
82.
Nishimura T, Simmons DJ, Mainous EG (1997) The origin of bone formed by heterotopic periosteal autografts. J Oral Maxillofac Surg 55:1265–1268PubMed
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 20:2044–2052PubMed
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 11:645–658PubMed
85.
Jeppsson C, Astrand J, Tagil M, Aspenberg P (2003) A combination of bisphosphonate and BMP additives in impacted bone allografts. Acta Orthop Scand 74:483–489PubMed
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 41:311–315PubMed
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 89:11740–11744PubMedCentralPubMed
88.
Hentunen TA, Cunningham NS, Vuolteenaho O, Reddi AH, Vaananen HK (1994) Osteoclast recruiting activity in bone matrix. Bone Miner 25:183–198PubMed
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 209:433–443PubMed
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 10:1681–1690PubMed
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 250:776–781PubMed
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 259:97–102PubMed
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 15:663–673PubMed
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 14:31–36PubMed
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.
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 77:75–83PubMed
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 281:20160–20170PubMed
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 19:575–589PubMed
99.
Cook SD (1999) Preclinical and clinical evaluation of osteogenic protein-1 (BMP-7) in bony sites. Orthopedics 22:669–671PubMed
100.
Seeherman H, Wozney JM (2005) Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev 16:329–345PubMed
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
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
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 8:485–490PubMedCentralPubMed
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 19:130–134PubMed
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 1976PubMed
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 1976PubMed
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 32:4393–4405PubMed
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 54:1209–1221PubMed
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 81:710–718PubMed
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 7:949–960PubMed
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 230:342–351PubMed
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 127:1755–1766PubMed
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 285:15577–15586PubMedCentralPubMed
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 88:1258–1265PubMed
115.
Vukicevic S, Grgurevic L, Oppermann H (2012) Whole blood-derived coagulum device for treating bone defects. US 8197840
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
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 13:273–280PubMed
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 52:1159–1167PubMed
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 26:2042–2051PubMedCentralPubMed
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 69:23–36PubMed
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 46:12238–12247PubMed
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
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 285:12169–12180PubMedCentralPubMed
124.
Vukicevic S, Sampath TK (2008) Bone morphogenetic proteins: from local to systemic therapeutics. Birkauser Verlag AG, Basel
125.
Zhang H, Bradley A (1996) Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122:2977–2986PubMed
126.
Grgurevic L, Macek B, Erjavec I, Mann M, Vukicevic S (2007) Urine release of systemically administered bone morphogenetic protein hybrid molecule. J Nephrol 20:311–319PubMed
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 22:681–692PubMedCentralPubMed
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 281:25509–25521PubMed
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 37:529–541PubMed
130.
Cuellar A, Reddi AH (2013) Cell biology of osteochondromas: bone morphogenic protein signalling and heparan sulphates. Int Orthop 37:1591–1596PubMed
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 26:1178–1187PubMed
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
Metadata
Title
The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing
Authors
Slobodan Vukicevic
Hermann Oppermann
Donatella Verbanac
Morana Jankolija
Irena Popek
Jasna Curak
Jelena Brkljacic
Martina Pauk
Igor Erjavec
Igor Francetic
Ivo Dumic-Cule
Mislav Jelic
Dragan Durdevic
Tomislav Vlahovic
Ruder Novak
Vera Kufner
Tatjana Bordukalo Niksic
Marija Kozlovic
Zrinka Banic Tomisic
Jadranka Bubic-Spoljar
Ivancica Bastalic
Smiljka Vikic-Topic
Mihaela Peric
Marko Pecina
Lovorka Grgurevic
Publication date
01-03-2014
Publisher
Springer Berlin Heidelberg
Published in
International Orthopaedics / Issue 3/2014
Print ISSN: 0341-2695
Electronic ISSN: 1432-5195
DOI
https://doi.org/10.1007/s00264-013-2201-1

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