Combined VEGF and LMP-1 delivery enhances osteoprogenitor cell differentiation and ectopic bone formation

Wang, Xiuli; Cui, Fuai; Madhu, Vedavathi; Dighe, Abhijit S.; Balian, Gary; Cui, Quanjun

doi:10.3109/08977194.2010.544656

Cited by 16 publications

(15 citation statements)

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“…CADM1 has been recently identified as a marker of higher bone forming capacity of MSCs [40]. The findings of this study shed light on possible mechanism for our earlier findings that D1 cells transiently (≤1 week) expressing VEGF and BMP-6 genes [32] or VEGF and LMP-1 genes [33] induced significantly greater bone formation at week 3 than that induced by D1 cells alone or D1 cells expressing any single gene. It appears from our present study (Fig.…”

Section: Discussionsupporting

confidence: 63%

“…In the last decade several investigators have shown that exogenous addition MSCs, VEGF and BMP synergistically enhances bone formation but the exact mechanism remains elusive. It is difficult to explain this synergy through VEGF induced increased angiogenesis since our previous studies on synergistic aspect [32]–[33] revealed that increase in angiogenesis did not always correlate with increase in osteogenesis. While complete inhibition of angiogenesis is known to inhibit bone formation [3]–[4] the number of vessels and VEGF expression levels are reported to be similar in non-union fractures and fractures that heal [38]–[39].…”

Section: Discussionmentioning

confidence: 96%

“…We have demonstrated earlier that cloned mouse bone marrow derived mesenchymal stem cells (mBMMSCs) (D1 cells) co-expressing human VEGF and BMP-6 genes or VEGF and lim mineralization protein 1 (LMP1) genes induce significantly greater osteogenesis in vivo in comparison with that induced by D1 cells alone or by D1 cells expressing only one of those genes [32]–[33]. LMP-1 is a known downstream signal transducer of BMP-6 signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

“…We have also shown recently that simultaneous activation of intracellular VEGF and BMP-6 pathways enhances osteogenic differentiation of human adipose derived stem cells (hADSCs) [35]. However, the exact mechanism of enhanced bone formation by transiently transfected D1 cells expressing VEGF and BMP-6 [32] or VEGF and LMP-1 [33] was not completely understood. It remained elusive as to what role was played by exogenously added D1 cells and what was contribution of VEGF and BMP-6 secreted by the cells in enhancing bone formation.…”

Section: Introductionmentioning

confidence: 99%

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BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation

Madhu

Dighe

et al. 2014

PLoS ONE

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Clinical trials on fracture repair have challenged the effectiveness of bone morphogenetic proteins (BMPs) but suggest that delivery of mesenchymal stem cells (MSCs) might be beneficial. It has also been reported that BMPs could not increase mineralization in several MSCs populations, which adds ambiguity to the use of BMPs. However, an exogenous supply of MSCs combined with vascular endothelial growth factor (VEGF) and BMPs is reported to synergistically enhance fracture repair in animal models. To elucidate the mechanism of this synergy, we investigated the osteoblastic differentiation of cloned mouse bone marrow derived MSCs (D1 cells) in vitro in response to human recombinant proteins of VEGF, BMPs (-2, -4, -6, -9) and the combination of VEGF with BMP-6 (most potent BMP). We further investigated ectopic bone formation induced by MSCs pre-conditioned with VEGF, BMP-6 or both. No significant increase in mineralization, phosphorylation of Smads 1/5/8 and expression of the ALP, COL1A1 and osterix genes was observed upon addition of VEGF or BMPs alone to the cells in culture. The lack of CD105, Alk1 and Alk6 expression in D1 cells correlated with poor response to BMPs indicating that a greater care in the selection of MSCs is necessary. Interestingly, the combination of VEGF and BMP-6 significantly increased the expression of ALP, COL1A1 and osterix genes and D1 cells pre-conditioned with VEGF and BMP-6 induced greater bone formation in vivo than the non-conditioned control cells or the cells pre-conditioned with either VEGF or BMP-6 alone. This enhanced bone formation by MSCs correlated with higher CADM1 expression and OPG/RANKL ratio in the implants. Thus, combined action of VEGF and BMP on MSCs enhances osteoblastic differentiation of MSCs and increases their bone forming ability, which cannot be achieved through use of BMPs alone. This strategy can be effectively used for bone repair.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation

Madhu

Dighe

et al. 2014

PLoS ONE

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“…The effectiveness of LMPs in inducing bone formation in vivo has been demonstrated, using different strategy to deliver the gene/peptide at the site where the bone healing was required (H.S. Lattanzi et al, 2008;Parrilla et al, 2010;Pola et al, 2004;Sangadala et al, 2009;Strohbach et al, 2008b;X. Wang et al, 2011;Yoon et al, 2004).…”

Section: Lim-mineralization Proteinsmentioning

confidence: 99%

Genes and Molecular Pathways of the Osteogenic Process

Lattanzi¹,

Bernardini²

2012

Osteogenesis

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Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect

Miller

McColl

Arul

et al. 2019

JAMA Facial Plast Surg

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IMPORTANCE Osseous craniofacial defects are currently reconstructed with bone grafting, rigid fixation, free tissue transfer, and/or recombinant human bone morphogenetic protein 2. Although these treatment options often have good outcomes, they are associated with substantial morbidity, and many patients are not candidates for free tissue transfer. OBJECTIVE To assess whether polysaccharide-based scaffold (PS) constructs that are cross-linked with smoothened agonist (SAG), vascular endothelial growth factor (VEGF), and bone morphogenetic protein 6 (BMP-6) would substantially increase bone regeneration. DESIGN, SETTING, AND PARTICIPANTS This animal model study was conducted at the University of Virginia School of Medicine Cui Laboratory from March 1, 2017, to June 30, 2017. Thirty-three 10-week-old female Lewis rats were acquired for the study. Bilateral nonsegmental critical-sized defects were created in the angle of rat mandibles. The defects were either left untreated or filled with 1 of the 9 PSs. The rats were killed after 8 weeks, and bone regeneration was evaluated using microcomputed tomographic imaging and mechanical testing. Analysis of variance testing was used to compare the treatment groups. MAIN OUTCOMES AND MEASURES Blinded analysis and computer analysis of the microcomputed tomographic images were used to assess bone regeneration. RESULTS In the 33 female Lewis rats, minimal healing was observed in the untreated mandibles. Addition of SAG was associated with increases in bone regeneration and bone density in all treatment groups, and maximum bone healing was seen in the group with BMP-6, VEGF, and SAG cross-linked to PS. For each of the 5 no scaffold group vs BMP-6, VEGF, and SAG cross-linked to PS group comparisons, mean defect bone regeneration was 4.14% (95% CI, 0.94%−7.33%) vs 66.19% (95% CI, 54.47%−77.90%); mean bone volume, 14.52 mm3 (95% CI, 13.07–15.97 mm3) vs 20.87 mm3 (95% CI, 14.73– 27.01 mm3); mean bone surface, 68.97 mm2 (95% CI, 60.08–77.85 mm2) vs 96.77 mm2 (95% CI, 76.11–117.43 mm2); mean ratio of bone volume to total volume, 0.11 (95% CI, 0.10–0.11) vs 0.15 (95% CI, 0.10–0.19); and mean connectivity density 0.03 (95% CI, 0.02–0.05) vs 0.32 (95% CI, 0.25–0.38). On mechanical testing, mandibles with untreated defects broke with less force than control mandibles in which no defect was made, although this force did not reach statistical significance. No significant difference in force to fracture was observed among the treatment groups. CONCLUSIONS AND RELEVANCE In this rat model study, activation of the hedgehog signaling pathway using smoothened agonist was associated with increased craniofacial bone regeneration compared with growth factors alone, including US Food and Drug Administration–approved recombinant human bone morphogenetic protein 2. Pharmaceuticals that target this pathway may offer a new reconstructive option for bony craniofacial defects as well as nonunion and delayed healing fractures.

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Combined VEGF and LMP-1 delivery enhances osteoprogenitor cell differentiation and ectopic bone formation

Cited by 16 publications

References 53 publications

BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation

BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation

Genes and Molecular Pathways of the Osteogenic Process

Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect

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