Since the discovery of osteoinduction in the early 20th century, innovative biomaterials with osteoinductive potential have emerged. Over the last 50 years, however, our ability to describe biological phenomena accurately has been improved dramatically by advancements in cell and molecular biology. The aim of this review is to divide the osteoinduction phenomenon into 3 principles: (1) mesenchymal cell recruitment, (2) mesenchymal differentiation to bone-forming osteoblasts, and (3) ectopic bone formation in vivo. Furthermore, this review formulates guidelines for in vitro and in vivo experimental testing for accurately defining new biomaterials as osteoinductive. The use of growth factors with osteoinductive potential in periodontal and oral surgery is discussed. These concepts and guidelines aim to guide the future direction of emerging biomaterials in bone regeneration.
BanerjeeCMcCabeLRChoiJYHiebertSWSteinJLSteinGS. (1997). Runt homology domain proteins in osteoblast differentiation: AML3/CBFA1 is a major component of a bone-specific complex. J Cell Biochem66:1-8.
6.
BarradasAMYuanHvan BlitterswijkCAHabibovicP (2011). Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms. Eur Cell Mater21:407-429.
7.
BarryFPMurphyJM (2004). Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol36:568-584.
8.
BegleyCTDohertyMJMollanRAWilsonDJ (1995). Comparative study of the osteoinductive properties of bioceramic, coral and processed bone graft substitutes. Biomaterials16:1181-1185.
9.
BoskeyALWrightTMBlankRD (1999). Collagen and bone strength. J Bone Miner Res14:330-335.
10.
BracciniAWendtDJaquieryCJakobMHebererMKeninsL. (2005). Three-dimensional perfusion culture of human bone marrow cells and generation of osteoinductive grafts. Stem Cells23:1066-1072.
11.
BurgerEHKlein-NulendJ (1999). Mechanotransduction in bone—role of the lacuno-canalicular network. FASEB J13 (Suppl):101S-112S.
12.
CarbajalKSSchaumburgCStrieterRKaneJLaneTE (2010). Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis. Proc Natl Acad Sci USA107:11068-11073.
13.
CatrosSZwetyengaNBareilleRBrouillaudBRenardMAmedeeJ. (2009). Subcutaneous-induced membranes have no osteoinductive effect on macroporous HA-TCP in vivo. J Orthop Res27:155-161.
14.
ChanCKChenCCLuppenCAKimJBDeBoerATWeiK. (2009). Endochondral ossification is required for haematopoietic stem-cell niche formation. Nature457:490-494.
15.
ChanRCMarinoVBartoldPM (2011). The effect of Emdogain (R) and platelet-derived growth factor on the osteoinductive potential of hydroxyapatite tricalcium phosphate. Clin Oral Investig [Epub ahead of print Oct 28, 2011].
16.
ChaudharyLRHofmeisterAMHruskaKA (2004). Differential growth factor control of bone formation through osteoprogenitor differentiation. Bone34:402-411.
17.
ChenuCColucciSGranoMZigrinoPBarattoloRZamboninG. (1994). Osteocalcin induces chemotaxis, secretion of matrix proteins, and calcium-mediated intracellular signaling in human osteoclast-like cells. J Cell Biol127:1149-1158.
De BariCDell’accioF (2008). Cell therapy: a challenge in modern medicine. Biomed Mater Eng18 (1 Suppl):11S-17S.
20.
DucyPZhangRGeoffroyVRidallALKarsentyG (1997). Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell89:747-754.
21.
DucyPSchinkeTKarsentyG (2000). The osteoblast: a sophisticated fibroblast under central surveillance. Science289:1501-1504.
22.
FiedlerJRodererGGuntherKPBrennerRE (2002). BMP-2, BMP-4, and PDGF-bb stimulate chemotactic migration of primary human mesenchymal progenitor cells. J Cell Biochem87:305-312.
23.
FierroFIllmerTJingDSchleyerEEhningerGBoxbergerS. (2007). Inhibition of platelet-derived growth factor receptor-beta by imatinib mesylate suppresses proliferation and alters differentiation of human mesenchymal stem cells in vitro. Cell Prolif40:355-366.
24.
FisherLWMcBrideOWTermineJDYoungMF (1990). Human bone sialoprotein. Deduced protein sequence and chromosomal localization. J Biol Chem265:2347-2351.
25.
FriedensteinAJChailakhjanRKLalykinaKS (1970). The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet3:393-403.
26.
GetachewRBallingerMLBurchMLReidJJKhachigianLMWightTN. (2010). PDGF beta-receptor kinase activity and ERK1/2 mediate glycosaminoglycan elongation on biglycan and increases binding to LDL. Endocrinology151:4356-4367.
27.
GiannoudisPVDinopoulosHTsiridisE (2005). Bone substitutes: an update. Injury36(Suppl 3):20-27.
28.
GonnermanKNBrownLSChuTM (2006). Effects of growth factors on cell migration and alkaline phosphatase release. Biomed Sci Instrum42:60-65.
29.
HabibovicPde GrootK (2007). Osteoinductive biomaterials–properties and relevance in bone repair. J Tissue Eng Regen Med1:25-32.
30.
HauschkaPVLianJBColeDEGundbergCM (1989). Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev69:990-1047.
31.
HeinzelKBenzCBleulCC (2007). A silent chemokine receptor regulates steady-state leukocyte homing in vivo. Proc Natl Acad Sci USA104:8421-8426.
32.
HorwitzEMLe BlancKDominiciMMuellerISlaper-CortenbachIMariniFC. (2005). Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy7:393-395.
33.
HugginsCB (1931). The phosphatase activity of transplants of the epithelium of the urinary bladder to the abdominal wall producing heterotopic ossification. Biochem J25:728-732.
34.
IsobeM (1995). [Characteristics and osteoinductive activity of bone morphogenetic protein (BMP) encapsulated with poly (DL-lactide-co-glycolide)]. Kokubyo Gakkai Zasshi62:506-512 [in Japanese].
35.
JabbarzadehEStarnesTKhanYMJiangTWirtelAJDengM. (2008). Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: a combined gene therapy-cell transplantation approach. Proc Natl Acad Sci USA105:11099-11104.
36.
KaiglerDAvilaGWisner-LynchLNevinsMLNevinsMRasperiniG. (2011). Platelet-derived growth factor applications in periodontal and peri-implant bone regeneration. Expert Opin Biol Ther11:375-385.
37.
KangJMKangSWLaWGYangYSKimBS (2010). Enhancement of in vivo bone regeneration efficacy of osteogenically undifferentiated human cord blood mesenchymal stem cells. J Biomed Mater Res A93:666-672.
38.
KaoSTScottDD (2007). A review of bone substitutes. Oral Maxillofac Surg Clin North Am19:513-521, vi.
39.
KimISSongYMHwangSJ (2010). Osteogenic responses of human mesenchymal stromal cells to static stretch. J Dent Res89:1129-1134.
40.
KimSJKimSYKwonCHKimYK (2007). Differential effect of FGF and PDGF on cell proliferation and migration in osteoblastic cells. Growth Factors25:77-86.
41.
KimSWMuiseAMLyonsPJRoHS (2001). Regulation of adipogenesis by a transcriptional repressor that modulates MAPK activation. J Biol Chem276:10199-10206.
42.
LangerR (2009). Perspectives and challenges in tissue engineering and regenerative medicine. Adv Mater21:3235-3236.
43.
LapidotTDarAKolletO (2005). How do stem cells find their way home?Blood106:1901-1910.
44.
LazarusHMHaynesworthSEGersonSLRosenthalNSCaplanAI (1995). Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant16:557-564.
45.
LazarusHMKocONDevineSMCurtinPMaziarzRTHollandHK. (2005). Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant11:389-398.
46.
LeeMHKimYJKimHJParkHDKangARKyungHM. (2003). BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. J Biol Chem278:34387-34394.
47.
LevanderG (1938). A study of bone regeneration. Surg Gynecol Obstet67:705-714.
48.
LiGCuiYMcIlmurrayLAllenWEWangH (2005). rhBMP-2, rhVEGF (165), rhPTN and thrombin-related peptide, TP508 induce chemotaxis of human osteoblasts and microvascular endothelial cells. J Orthop Res23:680-685.
49.
Lissenberg-ThunnissenSNde GorterDJSierCFSchipperIB (2011). Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop35:1271-1280.
50.
LiuZJZhugeYVelazquezOC (2009). Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem106:984-991.
51.
MassaguéJ (1996). TGFbeta signaling: receptors, transducers, and Mad proteins. Cell85:947-950.
52.
Mendez-FerrerSMichurinaTVFerraroFMazloomARMacarthurBDLiraSA. (2010). Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature466:829-834.
53.
MiyazonoKKusanagiKInoueH (2001). Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol187:265-276.
54.
MoorenREHendriksEJvan den BeuckenJJMerkxMAMeijerGJJansenJA. (2010). The effect of platelet-rich plasma in vitro on primary cells: rat osteoblast-like cells and human endothelial cells. Tissue Eng Part A16:3159-3172.
55.
NakashimaKZhouXKunkelGZhangZDengJMBehringerRR. (2002). The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell108:17-29.
56.
Nombela-ArrietaCRitzJSilbersteinLE (2011). The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol12:126-131.
57.
O’SullivanJD’ArcySBarryFPMurphyJMColemanCM (2011). Mesenchymal chondroprogenitor cell origin and therapeutic potential. Stem Cell Res Ther2:8.
58.
OhtakiHYlostaloJHForakerJERobinsonAPRegerRLShiodaS. (2008). Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses. Proc Natl Acad Sci USA105:14638-14643.
59.
OldbergAFranzenAHeinegardD (1986). Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc Natl Acad Sci USA83:8819-8823.
60.
OldbergAFranzenAHeinegardD (1988). The primary structure of a cell-binding bone sialoprotein. J Biol Chem263:19430-19432.
61.
OldershawRABaxterMALoweETBatesNGradyLMSoncinF. (2010). Directed differentiation of human embryonic stem cells toward chondrocytes. Nat Biotechnol28:1187-1194.
62.
PhinneyDGProckopDJ (2007). Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells25:2896-2902.
63.
PlaceESEvansNDStevensMM (2009). Complexity in biomaterials for tissue engineering. Nat Mater8:457-470.
RanlyDMMcMillanJKellerTLohmannCHMeunchTCochranDL. (2005). Platelet-derived growth factor inhibits demineralized bone matrix-induced intramuscular cartilage and bone formation. A study of immunocompromised mice. J Bone Joint Surg Am87:2052-2064.
66.
RanlyDMLohmannCHAndreacchioDBoyanBDSchwartzZ (2007). Platelet-rich plasma inhibits demineralized bone matrix-induced bone formation in nude mice. J Bone Joint Surg Am89:139-147.
67.
RonnstrandLHeldinCH (2001). Mechanisms of platelet-derived growth factor-induced chemotaxis. Int J Cancer91:757-762.
68.
RyooHMHoffmannHMBeumerTFrenkelBTowlerDASteinGS. (1997). Stage-specific expression of Dlx-5 during osteoblast differentiation: involvement in regulation of osteocalcin gene expression. Mol Endocrinol11:1681-1694.
69.
RyooHMLeeMHKimYJ (2006). Critical molecular switches involved in BMP-2-induced osteogenic differentiation of mesenchymal cells. Gene366:51-57.
70.
ShimonoKTungWEMacolinoCChiAHDidizianJHMundyC. (2011). Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med17:454-460.
TangYWuXLeiWPangLWanCShiZ. (2009). TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med15:757-765.
73.
TenenbaumHC (1987). Levamisole and inorganic pyrophosphate inhibit beta-glycerophosphate induced mineralization of bone formed in vitro. Bone Miner3:13-26.
74.
TyeCEHunterGKGoldbergHA (2005). Identification of the type I collagen-binding domain of bone sialoprotein and characterization of the mechanism of interaction. J Biol Chem280:13487-13492.
75.
UristMR (1965). Bone: formation by autoinduction. Science150(3698):893-899.
76.
UristMRMcLeanFC (1952). Osteogenetic potency and new-bone formation by induction in transplants to the anterior chamber of the eye. J Bone Joint Surg Am34(A):443-476.
77.
UristMRStratesBS (1971). Bone morphogenetic protein. J Dent Res50:1392-1406.
78.
UristMRSilvermanBFBuringKDubucFLRosenbergJM (1967). The bone induction principle. Clin Orthop Relat Res53:243-283.
79.
VordemvenneTPalettaJRHartensuerRPapTRaschkeMJOchmanS (2011). Cooperative effects in differentiation and proliferation between PDGF-BB and matrix derived synthetic peptides in human osteoblasts. BMC Musculoskelet Disord12:263.
80.
WeinrebMShinarDRodanGA (1990). Different patterns of alkaline phosphatase, osteopontin, and osteocalcin expression in developing rat bone visualized by in situ hybridization. J Bone Miner Res5:831-842.
81.
WennbergCHessleLLundbergPMauroSNarisawaSLernerUH. (2000). Functional characterization of osteoblasts and osteoclasts from alkaline phosphatase knockout mice. J Bone Miner Res15:1879-1888.
82.
WildemannBBurkhardtNLuebberstedtMVordemvenneTSchmidmaierG (2007). Proliferating and differentiating effects of three different growth factors on pluripotent mesenchymal cells and osteoblast like cells. J Orthop Surg Res2:27.
83.
XiaoGJiangDThomasPBensonMDGuanKKarsentyG. (2000). MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J Biol Chem275:4453-4459.
84.
YanagisawaMSuzukiNMitsuiNKoyamaYOtsukaKShimizuN (2007). Effects of compressive force on the differentiation of pluripotent mesenchymal cells. Life Sci81:405-412.
85.
YuXHsiehSCBaoWGravesDT (1997). Temporal expression of PDGF receptors and PDGF regulatory effects on osteoblastic cells in mineralizing cultures. Am J Physiol272(5Pt 1):C1709-C1716.
86.
ZhangWLiuHT (2002). MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res12:9-18.
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