Table 2.
Bone morphogenetic proteins 2 (keyword: BMP2 and osteoblast, 2006–2011 and published in English)
| Author | Type | Cell | Objective | Result |
|---|---|---|---|---|
| Hughes-Fulford and Li [135] | In vitro | MC3T3E1 osteoblast-like cells | To describe the sequential roles of FGF-2 in inducing gene expression, cell growth, and BMP-2 in gene expression and mineralization of bone | The ability of FGF-2 to re-program a mineralizing gene expression profile to one of proliferation suggests that FGF-2 plays a critical role of osteoblast growth in early fracture repair while BMP-2 is instrumental in stimulating mineralization |
| Kaewrichan et al. [136] | In vivo; nude mice | Marrow stromal cells | To develop culture conditions that permit a rapid increase in the number of marrow stromal cells while retaining or improving their potential for complete differentiation in vivo | FGF2 increased the pool of committed osteoblasts by up-regulating the Cbfa1/Runx2 gene. The later stages of bone formation seemed to be induced by Cbfa1/Runx2-downstream factors such as BMP2, ALP, collagen type I, bone sialoprotein and OC |
| Keibl et al. [138] | In vivo; femur of male rat | ASCs | To investigate bone healing upon administration of the growth factor BMP-2 embedded with ASCs in a locally applied fibrin matrix | Transplantation of ASC modulated the callus induction by BMP-2 to a normal volume |
| Lee et al. [139] | In vitro, in vivo | MC3T3-E1 pre-osteoblasts | To examine a 3D scaffold with embedded growth factor-delivering microspheres | Solid free-form fabrication scaffolds created by microstereolithography were superior to traditional scaffolds produced using a particulate leaching/gas foaming method. The scaffolds that released BMP2 promoted bone formation |
| Liu et al. [109] | In vitro | Marrow-derived mesenchymal stromal cells | To investigate the osteogenic and angiogenic effects of marrow-derived mesenchymal stromal cells when co-transfected (by means of lentivirus) the human angiopoietin-1 gene (hAng-1) and hBMPs | The combined gene therapy with hAng-1 and hBMP2 using lentivirally co-transfected MSCs is feasible |
| Liu et al. [109] | In vitro | Osteoblast | To investigate the role of type II BMP receptors in osteoblasts | The observed functional redundancy of type II BMP receptors in osteoblasts is novel information about the BMP signaling pathway essential for initiating osteoblast differentiation |
| Ono et al. [110] | In vivo; transgenic mice that overexpressed human WISP-1 in preosteoblasts | To determine the function of WISP-1 during osteogenesis, osteogenic bone marrow stromal cells | WISP-1 has a positive influence on bone cell differentiation and function and may work by enhancing the effects of BMP-2 to increase osteogenesis through a mechanism potentially involving binding to integrin α(5)β(1) | |
| Schofer et al. [146, 147] | In vitro | Mesenchymal stem cell differentiation of osteoblasts | To analyze whether these processes can be remodeled in an artificial PLLA-based nanofiber scaffold | The incorporation of BMP2 into PLLA-collagen type I nanofibers resulted in a decrease in diameter as well as pore sizes of the scaffold. Mesenchymal stem cells showed better adherence and a reduced proliferation on BMP-containing scaffolds |
| Carpenter et al. [111] | In vitro | Bone marrow-derived mesenchymal stem cells were harvested from the iliac crest of three human donors and tuber coxae of three equine donors | To compare the effect of genetic modification of human and equine bone marrow-derived mesenchymal stem cells with BMP2 or -7 or BMP2 and -7 on their osteoblastogenic differentiation in the presence or absence of dexamethasone | Genetically modified bone marrow-derived mesenchymal stem cells could be useful for cell-based delivery of BMPs to a site of bone formation |
| Chen et al. [74, 106] | In vitro | Osteoblasts | To understand the events of osteoblast differentiation induced by statins | Simvastatin can promote osteoblast viability and differentiation via membrane-bound Ras/Smad/Erk/BMP2 pathway. Statins stimulate osteoblast differentiation in vitro and may be a promising drug for the treatment of osteoporosis in the future |
| Honda et al. [108] | C2C12 mouse mesenchymal progenitor cells | To examine the potential role of PDZRN3 in the differentiation of C2C12 cells into osteoblasts | PDZRN3 plays an important role in negative feedback control of BMP2-induced osteoblast differentiation in C2C12 cells through inhibition of Wnt-β-catenin signaling | |
| Huang et al. [46, 124] | In vitro | Cultured osteoblasts | To investigate the effects of adiponectin on BMPs expression | Adiponectin enhances BMP2 expression in osteoblastic cells, and AdipoR1 receptor, AMPK, p38 and NF-kappaB signaling pathways may be involved in increasing BMP-2 expression by adiponectin |
| Ishibashi et al. [128] | In vitro | PDL cells, MC3T3-E1 osteoblastic cells | To analyze characteristics unique for PDL at a molecular level | Raise a possibility that PDL cells respond to BMP2 via a unique signaling pathway dependent on endoglin, which is involved in the osteoblastic differentiation and mineralization of the cells |
| Itoh et al. [100] | In vitro | MC3T3-E1 cells, primary osteoblast cells | To investigate the role of microRNAs to BMP2 | The down-regulation of microRNAs-208 in BMP2-stimulated osteoblast differentiation is an important part of the regulatory machinery involved in early osteogenesis |
| Kawasaki et al. [133] | In vivo; mouse model | To analyze osteogenic properties of HGF, particularly during BMP2-induced bone formation | Treatment with HGF prior to administration of BMP-2 induced cellular proliferation of mouse embryonic fibroblasts and did not influence subsequent osteoblast differentiation induced by BMP-2 | |
| Kim et al. [127] | In vitro | C2C12 cells | To demonstrate a stimulatory effect of tanshinone IIA isolated from the root of Salvia miltiorrhiza on the commitment of bi-potential mesenchymal precursor C2C12 cells into osteoblasts in the presence of BMP2 | Tanshinone IIA enhances the commitment of C2C12 cells into osteoblasts and their differentiation through synergistic cross talk between tanshinone IIA-induced p38 activation and BMP-2-induced Smad activation |
| Kim et al. [127] | In vitro | MC3T3-E1 pre-osteoblasts | To investigate osteoblast responses to high-power laser and combined irradiation with BMP2 treatment | High-power, low-level Nd:YAG laser increased osteoblast activity, very efficiently accelerating mineral deposition. Osteoinductive effect of laser is likely mediated by activation of BMP2-related signaling pathway |
| Ko et al. [129] | In vitro, in vivo; Sprague–Dawley rats | MG-63 cells | To assess the cytotoxicity of mineral trioxide aggregate (MTA) and BMP2 and the response of rat pulp tissue to MTA and BMP2 | The addition of BMP2 had a beneficial effect in vitro, reducing the initial cytotoxicity of freshly mixed MTA. However, the pulp reaction to a combination of MTA and BMP-2 was not significantly better than use of MTA alone |
| Mandal et al. [125] | In vitro | Mouse 2T3 pre-osteoblasts | To demonstrate a novel mechanism of BMP-2-induced osteoblast differentiation | A signaling pathway linking BMP-2 stimulated Nox4-derived physiological reactive oxygen species to BMP-2 expression and osteoblast differentiation |
| Seib et al. [142] | In vitro | C2C12s | To investigate the role of ECM physisorbed BMPs in inducing the differentiation of resident mesenchymal stem cells into osteoblasts | Physisorbed BMP2 is more active than diffusible BMP2. The current clinical practice of immobilizing BMPs on collagen type I scaffolds not only prolongs local delivery of the morphogen but could also enhance biological activity at the cellular level |
| Su et al. [107] | In vitro | MC3T3-E1 osteoblasts, primary cultured osteoblasts | To investigate the interaction between CYR61 and BMP-2 | CYR61 up-regulates BMP-2 mRNA and protein expression, resulting in enhanced cell proliferation and osteoblastic differentiation through activation of the α(v)β(3) integrin/integrin-linked kinase/ERK signaling pathway |
| Tseng et al. [121] | In vitro | Osteoblastic cells MG-63, hFOB, and bone marrow stromal cells M2-10B4 | To investigate the effects of hypoxia exposure on BMP2 expression in cultured osteoblasts | Hypoxia enhances BMP2 expression in osteoblasts by an HIF-1alpha-dependent mechanism involving the activation of integrin-linked kinase/Akt (1L-6-hydroxymethyl-chiro-inositol-2-[(R)-2-O-methyl-3-O-octadecyl carbonate]) and mammalian target of rapamycin pathways |
| Verrier et al. [120] | In vitro | hMSCs | To test the effect of platelet-released supernatant (PRS) on human MSCs differentiation towards an osteoblastic phenotype | The effect of PRS on human MSCs could be at least partially mediated by BMP-2. Activated autologous PRS could therefore provide an alternative to agents like recombinant bone growth factors by increasing osteoblastic differentiation of bone precursor cells at bone repair sites, although further studies are needed to fully support our observations |
| Zhao et al. [154] | In vivo; mandibular defects in rats | bMSCs | To investigate the effects of mandibular defects repaired by a tissue engineered bone complex with beta-TCP and BMP2 gene-modified bone marrow stromal cells (bMSCs) | BMP2 regional gene therapy together with beta-TCP scaffold could be used to promote mandibular repairing and bone regeneration |
| Zheng et al. [155] | In vitro, in vivo; femoral defects | MC3T3-E1 pre-osteoblasts | To demonstrate that metallic nanosilver particles (with a size of 20–40 nm)-PLGA composite grafts have strong antibacterial properties | Nanosilver of defined particle size is bactericidal without discernable in vitro and in vivo cytotoxicity or negative effects on BMP-2 osteoinductivity, making it an ideal antimicrobial for bone regeneration in infected wounds |
| Balmayor et al. [156] | In vitro | Osteo/myoblast cell line (C2C12) | To develop and test a novel injectable drug delivery system consisting of starch-poly-epsilon-caprolactone microparticles for inducing osteogenesis and requiring smaller amounts of BMP2 | Starch-poly-epsilon-caprolactone microparticles are suitable carriers for the incorporation and controlled release of glucocorticoids and growth factors. Specifically, they reduce the amount of BMP-2 needed and allow more sustained osteogenic effects |
| Degat et al. [140] | In vitro, in vivo; rats | C2C12 myoblasts | To explore the binding capacity of synthetic heparin-like dextran derivatives to rhBMP2 | The formation of the BMP-2/carboxymethylated dextran polymers grafted with high amounts of benzylamide (DMCB) complex may protect the protein from being inactivated. In rats in vivo, DMCB also stimulated ectopic calcification mediated by BMP-2 |
| Hou et al. [126] | In vitro | Osteoblast | To investigate the effect of ultrasound to BMP2 expression | Ultrasound increased BMP2 expression in osteoblasts via the PI3K, Akt, c-Fos/c-Jun, and AP-1 signaling pathway |
| Johnson et al. [112] | In vitro | To develop sustained release systems | The lipid microtube system is able to provide sustained delivery of biologically active BMP2 and thereby induce osteogenic differentiation | |
| Kim et al. [114] | In vitro | C2C12 pluripotential myoblasts | To test mechanical stretching enhances osteoblast differentiation in distraction osteogenesis by means of interaction with BMP2 induced cytokine stimulation | Specific levels of static stretching force increase cell proliferation and effectively stimulate the osteoblast differentiation of C2C12 cells in conjunction with BMP2 stimulation, thus indicating a synergistic interaction between mechanical strain and cytokine signaling |
| Liu et al. [89] | In vitro | Myoblastic murine cell lines, primary cells with osteoprogenitors | To test the sensitivity of cells to BMP2 would correlate with BMP receptor expression | Osteogenic sensitivity of muscle progenitors and provide a mechanistic insight into the variable response of different cell lineages to BMP2 |
| Schofer et al. [145] | In vitro | hMSCs | To analyze the impact of PLLA nanofibers on VEGF and BMP2 gene expression during the time course of hMSC differentiation towards osteoblasts | The PLLA nanofibers have little effect on growth factor production. An enhancement in gene expression of BMP2 and VEGF can be achieved by an incorporation of BMP2 into the PLLA nanofibers |
| Takase et al. [123] | In vitro | Osteoblastic MC3T3-E1 cells | To examine if PTH affects BMP2 expression and to clarify its involvement of the mevalonate pathway | PTH stimulated BMP-2 mRNA expression via the mevalonate pathway and ROK in osteoblastic MC3T3-E1 cells |
| Zhang et al. [97] | In vitro | Primary osteoblasts, osteoblast precursor cell lines 2T3, and MC3T3-E1 cells | To investigate the effect of BMP-2 on beta-catenin signaling | BMP2 may regulate osteoblast function in part through modulation of the beta-catenin signaling |
| Jager et al. [98] | In vitro | Bone marrow-derived human MSCs | To investigate interactions between dexamethasone and BMP2 for an osteoblastic differentiation of MSCs | BMP2 enhances dexamethasone/ascorbic acid/glycerolphosphate-induced osteogenic differentiation in mesenchymal bone marrow cells. Both agents interact in various ways and can modify osteoblastic bone formation |
| Kanzaki et al. [118] | In vitro | Osteoblast | To investigate the role of heparin in the biological activity of BMP | Heparin suppresses BMP2-BMP receptor binding, and inhibits BMP2 osteogenic activity in vitro |
| Laflamme and Rouabhia [141] | In vitro | Osteoblasts | To evaluate the effect of BMP2 and BMP7 homodimers and a mixture of BMP2/BMP7 homodimers on osteoblast adhesion and growth following culture on a collagen scaffold | The BMP2, BMP7, and a mixture of BMP2/BMP7 all promoted osteoblast growth on the collagen scaffold, with the mixture of BMP2/BMP7 enhancing the most growth. BMP2, BMP7, and the mixture of BMP2/BMP7 could promote bone regeneration via different mechanisms involving IL-6 and MMP inhibitors |
| Lavery et al. [96] | In vitro | hMSCs | To evaluate receptor utilization by BMP-2, BMP-4, BMP-6, and BMP-7 in primary hMSCs | Different mechanisms for BMP2/4- and BMP6/7-induced osteoblastic differentiation in primary hMSCs |
| Luppen et al. [104] | In vitro | To better understand how glucocorticoids regulate BMPs | Glucocorticoids regulate BMP2 via a far-downstream domain, and activation of Smad, not ALP, best predicts the pro-mineralization potential of rhBMPs | |
| Schwartz et al. [99] | In vitro | hMSCs | To test PEMF, enhances osteogenesis of MSCs in the presence of an inductive stimulus like BMP2 | PEMF enhances osteogenic effects of BMP2 on MSCs cultured on calcium phosphate substrates, suggesting that PEMF will improve MSC response to BMP2 in vivo in a bone environment |
| Singhatanadgit et al. [87] | In vitro | Three different bone cell samples | To examine the effects of BMPR-IB knockdown on BMP-induced osteoblast-associated genes | The possibility that BMP receptor-IB could be a therapeutic target for enhancing bone regeneration in vivo |
| Samee et al. [132] | In vitro, in vivo | Human periosteum-derived cells were transfected with BMP-2, VEGF, BMP-2 + VEGF | To evaluate the feasibility and efficacy of BMP2 and/or VEGF on periosteal cell differentiation to osteoblasts in vitro and ectopic bone formation in vivo | VEGF might enhance BMP2-induced bone formation through modulation of angiogenesis |
| Susperregui et al. [85] | In vitro | Pluripotent mesenchymal C2C12 cells | To test BMP2 rapidly down-regulated PTHrP gene expression through a transcriptional mechanism | BMP2 down-regulation of PTHrP could facilitate terminal differentiation of osteoblasts |
| Van der Zande et al. [130] | In vitro | Osteoblast-like cells from rat bone marrow | To investigate the combined application of TGFbeta-1 and BMP2 to stimulate osteogenic expression in vitro | BMP-2 is the most suitable candidate for osteogenic stimulation of rat bone marrow cells |
| Zanotti et al. [119] | In vitro | ST-2 murine stromal cell lines, primary cultures of murine calvarial osteoblasts | To determine whether gremlin has direct effects in osteoblasts, independent of its BMP binding activity | Gremlin inhibits BMP-2 signaling and activity, and does not have independent actions on ERK signaling in osteoblasts |
| Cowan et al. [103, 143] | In vitro | C2C12 myoblasts were transduced with AdLacZ, AdNell-1, AdBMP-2, or AdNell-1 + AdBMP-2 overexpression viruses | To show Nell-1 and BMP-2 synergistically enhanced osteogenic differentiation of myoblasts and phosphorylated the JNK MAPK pathway | Osteochondral specificity of Nell-1 signaling and the potential therapeutic effects of enhanced BMP-2 action with coordinated Nell-1 delivery |
| Cowan et al. [103, 143] | In vitro | MC3T3-E1 osteoblasts | To examine the utility of microcomputed tomography over conventional techniques in the evaluation of the BMP2 dose response effect in a 3D in vitro culture system and in an established calvarial defect model | The utility of microcomputed tomography analysis as a beneficial addition to existing techniques for objective evaluation of bone tissue engineering and regeneration |
| Ding et al. [88] | In vivo | MSCs | To investigate the encapsulation of BMP-2 gene-modified MSCs in alginate-poly-l-lysine microcapsules for the persistent delivery of BMP2 to induce bone formation | The nonautologous BMP2 gene-transfected stem cells are of potential utility for enhancement of bone repair and bone regeneration in vivo |
| Gersbach et al. [90] | In vitro, in vivo | Osteoblast | To investigate the relative efficacy of different strategies for inducing osteoblastic differentiation | BMP2 stimulated osteoblastic markers faster and to a greater extent than Runx2. Runx2-engineered cells did not utilize paracrine signaling via secreted osteogenic factors, in contrast to cells overexpressing BMP-2 |
| Li et al. [144] | In vivo; canine model | To investigate bone regeneration by implantation of ADSCs expressing BMP2 | ADSCs modified by the BMP-2 gene can enhance the repair of critical-sized bone defects in large animals | |
| Liu et al. [92, 162] | In vitro | RD-C6 cells | To investigate the molecular mechanism underlying the differentiation of osteoblasts and chondroblasts | BMP-2 induces Runx2-deficient cells to express markers related to osteoblast and chondroblast differentiation using a Runx2-independent pathway, but it failed to induce these cells to differentiate into bone-forming osteoblasts and mature chondrocytes |
| Maegawa et al. [134] | In vitro | MSCs from rat bone marrow | To investigate the culture conditions that contributed to extensive osteoblastic differentiation | The number of responding cells or immature osteoblasts was increased by the supplementation of FGF-2 in the early phase of the culture and that these cells can show osteoblastic differentiation, of which capability was augmented by BMP-2 in the late phase |
| Minamizato et al. [117] | In vitro | MC3T3-E1 osteoblastic cells | To elucidate the role of CCN3/NOV in osteoblast differentiation | CCN3 exerts inhibitory effects on BMP-2-induced osteoblast differentiation by its involvement of the BMP and Notch signaling pathways |
| Mölders et al. [116] | In vitro | MC3T3-E1 cells | To analyze effects of the Ni-containing steel 316L and major metal constituents thereof on BMP2-induced alkaline phosphatase (ALP) | Cells contacting 316L steel are exposed to increased concentrations of Ni, which suffice to impair BMP2-induced ALP activity. Zn2+, as a competitor of this inhibition, may help to restore normal osteoblastic function and bone development under these conditions |
| Turhani et al. [137] | In vitro | Osteosarcoma cells (SaOS-2) | To examine whether extracellular matrix compartments and osteoinductive factors could further ameliorate the bioactivity of the scaffold | The combination of collagen type I and exogenous rhBMP-2 did not ameliorate the bioactivity of hydroxyapatite calcified from red algae in the initial period of cultivation |
| Yang et al. [115] | In vitro | Murine pre-myoblast C2C12 cells | To investigate the role of deltalEF1 to BMP2 | DeltaEF1 acts as a potent inhibitor of BMP-2-induced osteogenesis in vitro, in part, by differentially regulating the AP-1 signaling pathway |
| Gutierrez al. [113] | In vivo | Mouse myoblast cell line C2C12 | To analyze and characterize the proteoglycan populations that are induced in C2C12 cells upon osteoblastic differentiation produced by BMP-2 | The results are the first biochemical evidence and analysis for the effect of BMP-2 on the synthesis of proteoglycan during osteogenic conversion of myoblasts and suggest a role for decorin in cell response to BMP-2 |
| Seol et al. [148] | In vitro | Osteoblast-like MC3T3-E1 cells | To test BMP2 linked to titanium surfaces | Biochemical modifications of titanium surfaces can enhance the rate of bone healing as compared with untreated Ti surfaces |
| Singhatanadgit et al. [131] | In vitro | Primary human bone cell | To examined the effects of TGF-beta1, FGF-2, and PDGF-AB on BMP receptor expression and BMP-2-mediated osteoblast functions | Increased BMP receptor-IB by TGF-beta1, FGF-2, and PDGF-AB significantly enhances BMP-2-induced osteogenic functions in vitro, suggesting that they might positively modulate bone formation by up-regulating BMPR-IB in vivo |
| Suzuki et al. [102] | In vitro | MC3T3-E1 osteoblast-like cells | To study the role of Pi transport in BMP-2-induced matrix calcification | BMP-2 also stimulates Pi transport activity through a selective increase in expression of type III Pi transporters Pit-1. In MC3T3-E1 cells, this effect is mediated by the JNK pathway and plays an essential role in bone matrix calcification induced by BMP-2 |
| Zhao et al. [91] | In vitro | Human MSCs, murine pre-myoblast C2C12 cells | To test that PKA pathway is involved in osteogenesis | Activation of the PKA pathway may be one of key BMP-2-activated signaling events that lead to osteogenesis and that downregulation of PKIgamma may be prerequisite for the PKA activation during the osteoblastic differentiation of precursor cells |