The Role of Bone Morphogenetic Proteins in Bone Healing

Abstract

The discovery of the bone morphogentic proteins (BMPs) was a big step forward within the knowledge in bone physiology. BMPs are members of a large group of growth factors, the transforming growth factor-β (TGF-β) superfamily. BMPs are growth and differentiation factors which play a pivotal role at all stages in the complex process of embryonic bone formation and adult bone repair. The BMPs stimulate the chemotaxis, proliferation, and differentiation of mesenchymal stem cells resulting in a well controlled formation of bone. Their potential in enhancing bone repair has been demonstrated successfully in animals resulting in the development of BMPs for clinical applications. Before clinical introduction, questions concerning the appropriate dose, carrier delivery system, local and systemic safety had to be addressed, as understanding of the biological and cellular mechanisms of BMPs is essential for their usage in clinical practice.

Key words

BMPs - fracture healing - biological and cellular mechanisms

References

• 1 Akamaru T, Suh D, Boden S D, Kim H S, Minamide A, Louis-Ugbo J. Simple carrier matrix modifications can enhance delivery of recombinant human bone morphogenetic protein-2 for posterolateral spine fusion.  Spine. 2003;  28 429-434
• 2 Balemans W, Van Hul W. Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators.  Dev Biol. 2002;  250 231-250
• 3 Blattert T R, Delling G, Dalal P S, Toth C A, Balling H, Weckbach A. Successful transpedicular lumbar interbody fusion by means of a composite of osteogenic protein-1 (rhBMP-7) and hydroxyapatite carrier: a comparison with autograft and hydroxyapatite in the sheep spine.  Spine. 2002;  27 2697-2705
• 4 Boden S D, Zdeblick T A, Sandhu H S, Heim S E. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report.  Spine. 2000;  25 376-381
• 5 Boyan B D, Lohmann C H, Somers A. et al . Potential of porous poly-D,L-lactide-co-glycolide particles as a carrier for recombinant human bone morphogenetic protein-2 during osteoinduction in vivo.  J Biomed Mater Res. 1999;  46 51-59
• 6 Boyne P J, Marx R E, Nevins M. et al . A feasibility study evaluating rhBMP-2/absorbable collagen sponge for maxillary sinus floor augmentation.  Int J Periodontics Restorative Dent. 1997;  17 11-25
• 7 Cho T J, Gerstenfeld L C, Einhorn T A. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing.  J Bone Miner Res. 2002;  17 513-520
• 8 Cook S D, Baffes G C, Wolfe M W, Sampath T K, Rueger D C. Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model.  Clin Orthop. 1994;  301 302-312
• 9 Cook S D, Wolfe M W, Salkeld S L, Rueger D C. Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates.  J Bone Joint Surg [Am]. 1995;  77 734-750
• 10 Friedlaender G E, Perry C R, Cole J D. et al . Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions.  J Bone Joint Surg [Am]. 2001;  83 (Suppl 1) 151-158
• 11 Geesink R G, Hoefnagels N H, Bulstra S K. Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect.  J Bone Joint Surg [Br]. 1999;  81 710-718
• 12 Gerstenfeld L C, Cullinane D M, Barnes G L, Graves D T, Einhorn T A. Fracture healing as a post-natal developmental process: Molecular, spatial, and temporal aspects of its regulation.  J Cell Biochem. 2003;  88 873-884
• 13 Gitelman S E, Kobrin M S, Ye J Q, Lopez A R, Lee A, Derynck R. Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo.  J Cell Biol. 1994;  126 1595-1609
• 14 Govender S, Csimma C, Genant H K. et al . 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]. 2002;  84 2123-2134
• 15 Groeneveld E H, Burger E H. Bone morphogenetic proteins in human bone regeneration.  Eur J Endocrinol. 2000;  142 9-21
• 16 Ide H, Yoshida T, Matsumoto N. et al . Growth regulation of human prostate cancer cells by bone morphogenetic protein-2.  Cancer Res. 1997;  57 5022-5027
• 17 Ishidou Y, Kitajima I, Obama H. et al . Enhanced expression of type I receptors for bone morphogenetic proteins during bone formation.  J Bone Miner Res. 1995;  10 1651-1659
• 18 Itoh K, Udagawa N, Katagiri T. et al . Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand.  Endocrinology. 2001;  142 3656-3662
• 19 Itoh S, Itoh F, Goumans M J, ten Dijke P. Signaling of transforming growth factor-beta family members through Smad proteins.  Eur J Biochem. 2000;  267 6954-6967
• 20 Jingushi S, Urabe K, Okazaki K. et al . Intramuscular bone induction by human recombinant bone morphogenetic protein-2 with beta-tricalcium phosphate as a carrier: in vivo bone banking for muscle-pedicle autograft.  J Orthop Sci. 2002;  7 490-494
• 21 Johnsson R, Stromqvist B, Aspenberg P. Randomized radiostereometric study comparing osteogenic protein-1 (BMP-7) and autograft bone in human noninstrumented posterolateral lumbar fusion: 2002 Volvo Award in clinical studies.  Spine. 2002;  27 2654-2661
• 22 Kawabata M, Imamura T, Inoue H. et al . Intracellular signaling of the TGF-beta superfamily by Smad proteins.  Ann NY Acad Sci. 1999;  886 73-82
• 23 Laitinen M, Jortikka L, Halttunen T. et al . Measurement of total and local bone morphogenetic protein concentration in bone tumours.  Int Orthop. 1997;  21 188-193
• 24 Laursen M, Hoy K, Hansen E S, Gelineck J, Christensen F B, Bunger C E. Recombinant bone morphogenetic protein-7 as an intracorporal bone growth stimulator in unstable thoracolumbar burst fractures in humans: preliminary results.  Eur Spine J. 1999;  8 485-490
• 25 Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of TGF-beta/BMP signaling.  J Cell Physiol. 2001;  187 265-276
• 26 Poynton A R, Lane J M. Safety profile for the clinical use of bone morphogenetic proteins in the spine.  Spine. 2002;  27 S40-S48
• 27 Reddi A H. Role of morphogenetic proteins in skeletal tissue engineering and regeneration.  Nat Biotechnol. 1998;  16 247-252
• 28 Ripamonti U, van den Heever B, Sampath T K, Tucker M M, Rueger D C, Reddi A H. Complete regeneration of bone in the baboon by recombinant human osteogenic protein-1 (hOP-1, bone morphogenetic protein-7).  Growth Factors. 1996;  13 273-289
• 29 Ripamonti U, Van Den H B, Crooks J. et al . Long-term evaluation of bone formation by osteogenic protein 1 in the baboon and relative efficacy of bone-derived bone morphogenetic proteins delivered by irradiated xenogeneic collagenous matrices.  J Bone Miner Res. 2000;  15 1798-1809
• 30 Rosier R N, O'Keefe R J, Hicks D G. The potential role of transforming growth factor beta in fracture healing.  Clin Orthop. 1998;  355 (Suppl) 294-300
• 31 Sampath T K, Maliakal J C, Hauschka P V. et al . Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro.  J Biol Chem. 1992;  267 20352-20362
• 32 Sampath T K, Reddi A H. Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation.  Proc Natl Acad Sci U S A. 1981;  78 7599-7603
• 33 Sandhu H S, Kanim L E, Kabo J M. et al . Effective doses of recombinant human bone morphogenetic protein-2 in experimental spinal fusion.  Spine. 1996;  21 2115-2122
• 34 Schwartz Z, Somers A, Mellonig J T. et al . Addition of human recombinant bone morphogenetic protein-2 to inactive commercial human demineralized freeze-dried bone allograft makes an effective composite bone inductive implant material.  J Periodontol. 1998;  69 1337-1345
• 35 Soda H, Raymond E, Sharma S. et al . Antiproliferative effects of recombinant human bone morphogenetic protein-2 on human tumor colony-forming units.  Anticancer Drugs. 1998;  9 327-331
• 36 Urist M R. Bone: Formation by autoinduction.  Science. 1965;  150 893-899
• 37 Valentin-Opran A, Wozney J, Csimma C, Lilly L, Riedel G E. Clinical evaluation of recombinant human bone morphogenetic protein-2.  Clin Orthop. 2002;  395 110-120
• 38 von Bubnoff A, Cho K W. Intracellular BMP signaling regulation in vertebrates: pathway or network?.  Dev Biol. 2001;  239 1-14
• 39 Wang E A, Rosen V, Cordes P. et al . Purification and characterization of other distinct bone-inducing factors.  Proc Natl Acad Sci USA. 1988;  85 9484-9488
• 40 Wozney J M, Rosen V. Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair.  Clin Orthop. 1998;  346 26-37
• 41 Wozney J M, Rosen V, Celeste A J. et al . Novel regulators of bone formation: molecular clones and activities.  Science. 1988;  242 1528-1534