Recombinant bone morphogenetic protein-2 induces up-regulation of vascular endothelial growth factor and interleukin 6 in human pre-osteoblasts: Role of reactive oxygen species

Akeel, Sara; El‐Awady, Ahmed; Hussein, Khaled A.; Refaey, Mona El; Elsalanty, Mohammed; Sharawy, Mohamed; Al‐Shabrawey, Mohamed

doi:10.1016/j.archoralbio.2011.10.002

Cited by 26 publications

(26 citation statements)

References 34 publications

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“…50 We assessed ROS generation in NIH3T3 cells treated with NELL-1 -BMP2. As documented in previous studies in other cell types, 29,30 BMP2 increased ROS generation in a dose-dependent manner. Interestingly, NELL-1 significantly reduced ROS generation induced by BMP2 (Fig.…”

Section: Nell-1 Inhibits Bmp2 Induced Inflammatory Response In Vitro supporting

confidence: 86%

“…26,28 Moreover, in vitro assays have demonstrated that BMP2-induced inflammation is detectable in various cell types, such as endothelial cells, fibroblasts, 29 and preosteoblasts. 30 On a cellular level, BMP2 is known to be chemotactic for lymphocytes, monocytes, and macrophages. 31 Mechanistically, BMP2's induction of inflammation is known to be mediated through a reactive oxygen species (ROS)-dependent mechanism, by the generation of ROS in endothelial cells and preosteoblasts.…”

mentioning

confidence: 99%

“…31 Mechanistically, BMP2's induction of inflammation is known to be mediated through a reactive oxygen species (ROS)-dependent mechanism, by the generation of ROS in endothelial cells and preosteoblasts. 30 Thus and in summary, BMP2-induced inflammation is a well-studied phenomenon and potentially life threatening complication, attributable to an increase in inflammatory cell chemotaxis and an increase in ROS generation among other potential mechanisms.…”

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confidence: 99%

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BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1

Shen

James

Zara

et al. 2013

Tissue Engineering Part A

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Bone-morphogenetic protein 2 (BMP2) is currently the only Food and Drug Administration-approved osteoinductive growth factor used in clinical settings for bone regeneration and repair. However, the use of BMP2 is encumbered by numerous clinical complications, including postoperative inflammation and life-threatening cervical swelling. Thus, methods to prevent BMP2-induced inflammation would have far-reaching clinical implications toward improving current BMP2-based methods for bone regeneration. For the first time, we investigate the potential role of the growth factor Nel-like molecule-1 (NELL-1) in inhibiting BMP2-induced inflammation. Adult rats underwent a femoral bone onlay procedure, treated with either BMP2 protein (4 mg/mL), NELL-1 protein (4 mg/mL), or both proteins combined. Animals were evaluated at 3, 7, and 14 days postoperatively by histology, histomorphometry, immunohistochemistry, and real-time PCR for markers of inflammation (TNFa, IL6). The relative levels of TNFa and IL6 in serum were also detected by ELISA. The mechanism for NELL-1's antiinflammatory effect was further assessed through examining inflammatory markers and generation of reactive oxygen species (ROS) in the mouse embryonic fibroblast NIH3T3 cells. BMP2 significantly induced local inflammation, including an early and pronounced polymorphonuclear cell infiltration accompanied by increased expression of TNFa and IL6. Treatment with NELL-1 alone elicited no significant inflammatory response. However, NELL-1 significantly attenuated BMP2-induced inflammation by all markers and at all timepoints. These local findings were also confirmed using systemic serum inflammatory biomarkers (TNFa, IL6). In each case, NELL-1 fully reversed BMP2-induced systemic inflammation. Lastly, our findings were recapitulated in vitro, where NELL-1 suppressed BMP2 induced expression of inflammatory markers, as well as NF-kB transcriptional activity and generation of ROS. BMP2-induced inflammation is a serious public health concern with potentially life-threatening complications. In the present study, we observed that the growth factor, NELL-1, significantly attenuates or completely reverses BMP2-induced inflammation. The mechanisms of NELL-1's anti-inflammatory effect are only partially elucidated, and may include reduction of NF-kB transcriptional activity or ROS generation.

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Section: Nell-1 Inhibits Bmp2 Induced Inflammatory Response In Vitro supporting

confidence: 86%

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confidence: 99%

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confidence: 99%

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BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1

Shen

James

Zara

et al. 2013

Tissue Engineering Part A

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“…Anti-oxidants that can inhibit the oxidative processes can protect retinal cells from ischemic/hypoxic insults, a crucial factor in inducing RNV during ischemic retinopathy. In particular, treatment using anti-oxidants such as vitamin E and lutein, inhibition of NADPH oxidase or related signaling pathways, and administration of catalase and SOD are possible therapeutic regimens for RNV [107,122]. It has recently been observed that mice with targeted deletion of superoxide dismutase 1 (Sod1 −/− ) mice show many of the features of AMD, including spontaneous development of choroidal NV [123,124].…”

Section: Growth Factors and Retinal Neovascularizationmentioning

confidence: 99%

Targeting neovascularization in ischemic retinopathy: recent advances

Al‐Shabrawey

El‐Sherbiny

Nussbaum

et al. 2013

Expert Review of Ophthalmology

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Pathological retinal neovascularization (RNV) is a common micro-vascular complication in several retinal diseases including retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration and central vein occlusion. The current therapeutic modalities of RNV are invasive and although they may slow or halt the progression of the disease they are unlikely to restore normal acuity. Therefore, there is an urgent need to develop treatment modalities, which are less invasive and therefore associated with fewer procedural complications and systemic side effects. This review article summarizes our understanding of the pathophysiology and current treatment of RNV in ischemic retinopathies; lists potential therapeutic targets; and provides a framework for the development of future treatment modalities.

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“…Some investigators suggested that BMP signaling might play a role in retinal vascular homeostasis (Mathura et al, 2000) as well as diabetes induced-vascular dysfunction such as atherosclerosis (Csiszar et al, 2009; Derwall et al, 2012; Pi et al, 2012). The vascular effect of BMP signaling pathway has been correlated to its ability to induce oxidative stress, inflammatory and angiogenic responses (Akeel et al, 2012; Csiszar et al, 2006; Csiszar et al, 2009; Liberman et al, 2011). The relevance of BMPs in angiogenesis is illustrated by the discovery of BMP endothelial cell precursor derived regulator (BMPER), which is an extracellular regulator of BMPs required for proper BMP signaling (Kelley et al, 2009; Moser et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Bone morphogenetic protein 2: A potential new player in the pathogenesis of diabetic retinopathy

Hussein¹,

Choksi²,

Akeel³

et al. 2014

Experimental Eye Research

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Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus. Vision loss in DR principally occurs due to breakdown of the blood-retinal barrier (BRB), leading to macular edema, retinal detachment and inner retinal and vitreous hemorrhage. Several growth factors have been shown to play crucial role in the development of these vascular changes; however, the cellular and molecular mechanisms of DR are not yet fully revealed. In the current study we investigated the role of bone morphogenetic protein-2 (BMP2) in DR. We examined the changes in the protein levels of BMP2 in human vitreous and retina in addition to the mouse retina of streptozotocin-induced diabetes. To detect the source of BMP2 during diabetes, human retinal endothelial cells (hRECs) were subjected to high glucose (HG) for 5 days and levels of BMP2 protein were analyzed in conditioned media of these cells relative to control. We also evaluated the effect of BMP2 on the levels of VEGF in cultured rat Müller cells (rMC1). In addition, we tested the pro-inflammatory effects of BMP2 by examining its effect on leukocyte adhesion to cultured hRECs, and levels of adhesion molecules and cytokines production. Finally, the effect of different concentrations of BMP2 on permeability of confluent monolayer of hRECs was evaluated using FITC-Dextran flux permeability assay and by measuring Transcellular Electrical Resistance (TER) using Electric Cell-substrate Impedance Sensing (ECIS). Our results show, for the first time, the up-regulation of BMP2 in diabetic human and mouse retinas in addition to its detection in vitreous of patients with proliferative DR (72±7 pg/ml). In vitro, hRECs showed upregulation of BMP2 in HG conditions suggesting that these cells are a potential source of BMP2 in diabetic conditions. Furthermore, BMP2 induced VEGF secretion by Müller cells in-vitro; and showed a dose response in increasing permeability of cultured hRECs. Meanwhile, BMP2 pro-inflammatory effects were recognized by its ability to induce leukocyte adhesion to the hRECs, intercellular adhesion molecule-1 (ICAM-1) and upregulation of interleukin-6 and 8 (IL-6 and IL-8). These results show that BMP2 could be a contributing growth factor to the development of microvascular dysfunction during DR via enhancing both pro-angiogenic and inflammatory pathways. Our findings suggest BMP2 as a potential therapeutic target to prevent/treat DR.

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Recombinant bone morphogenetic protein-2 induces up-regulation of vascular endothelial growth factor and interleukin 6 in human pre-osteoblasts: Role of reactive oxygen species

Cited by 26 publications

References 34 publications

BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1

BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1

Targeting neovascularization in ischemic retinopathy: recent advances

Bone morphogenetic protein 2: A potential new player in the pathogenesis of diabetic retinopathy

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