Mohammed E Elsalanty

Georgia Regents University, Augusta, Georgia, United States

Are you Mohammed E Elsalanty?

Claim your profile

Publications (54)78.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Selective serotonin reuptake inhibitor (SSRI) use in pregnancy has been linked to craniofacial birth defects. Little is known about the effects of serotonin or SSRIs on craniofacial development. Here, we provide evidence that citalopram (SSRI) alters the osteogenic profile of murine calvarial cells and leads to craniofacial dysmorphology.Methods We used mouse calvarial pre-osteoblast cells (MC3T3-E1) to study the biochemical profile (microarray and quantitative reverse transcription polymerase chain reactions) after treatment with a titrated dose of citalopram. We used C57BL-6 wild-type breeders to produce litters treated with a clinical dose of citalopram during the third trimester of pregnancy. We used micro-computed tomography and morphometric measures to determine effects on craniofacial development.ResultsControls included untreated cells and age matched untreated litters. We observed decreases in proliferation and increases in alkaline phosphatase activity after citalopram exposure. We confirmed altered expression of genes linked to osteogenesis including Ocn and significant increase in expression of Alp after 7 days of treatment. Our data suggest altered expression of several genes related to craniofacial development (Fgf2, Fgfr2, Tgfβr2 Irs1, Igf1) and statistically significant changes in expression for (Col2a1, Gdf6, Hmox1, and Notch1). We also observed changes in regulation of the serotonin pathway (Sert, Tph1, Tph2, Htr2a, Lrp5) after treatment with citalopram. After in utero exposure to citalopram, mice displayed shorter narrow snouts, more globular skulls and several craniofacial anomalies.Conclusion Our results provide confirmatory evidence that citalopram exposure is associated with cellular and morphological alterations of the craniofacial complex, which may have important implications for use during pregnancy. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 10/2014; · 2.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study compared biomechanical patterns between finite element models (FEM) and a fresh dog mandible tested under molar and incisal physiological loads in order to clarify the effect of the bone transport distraction osteogenesis surgical process. Three FEM of dog mandibles were built in order to evaluate the effects of bone transport distraction osteogenesis. The first model evaluated the mandibular response under two physiological loads resembling bite processes. In the second model, a 5.0 cm bone defect was bridged with a bone transport reconstruction plate (BTRP). In the third model, new regenerated bony tissue was incorporated within the defect to mimic the surgical process without the presence of the device. Complementarily, a mandible of a male American foxhound dog was mechanically tested in the laboratory both in the presence and absence of a BTRP, and mechanical responses were measured by attaching rosettes to the bone surface of the mandible to validate the FEM predictions. The relationship between real and predicted values indicates that the stress patterns calculated using FEM is a valid predictor of the biomechanics of the bone transport distraction osteogenesis procedures. The present study provides an interesting correlation between the stiffness of the device and the biomechanical response of the mandible affected for bone transport.
    Journal of biomechanical engineering. 08/2014;
  • M. ELSALANTY
    IADR General Session and Exhibition 2014; 06/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Skeletal injury is a major clinical challenge accentuated by the decrease of bone marrow-derived mesenchymal stem/stromal cells (BMSCs) with age or disease. Numerous experimental and clinical studies have revealed that BMSCs hold great promise for regenerative therapies due to their direct osteogenic potential and indirect trophic/paracrine actions. Increasing evidence suggests that stromal cell-derived factor-1 (SDF-1) is involved in modulating the host response to the injury. Common problems with BMSC therapy include poor cell engraftment, which can be addressed by total body irradiation (TBI) prior to transplantation. In this study, we tested the hypothesis that direct tibial transplantation of BMSCs drives endogenous bone formation in a dose-dependent manner, which is enhanced by TBI, and investigated the potential role of SDF-1 in facilitating these events. We found that TBI is permissive for transplanted BMSCs to engraft and contribute to new bone formation. Bone marrow (BM) interstitial fluid analysis revealed no differences of SDF-1 splice variants in irradiated animals compared to controls, despite the increased mRNA and protein levels expressed in whole BM cells. This correlated with increased dipeptidyl peptidase IV (DPPIV) activity and the failure to induce chemotaxis of BMSCs in vitro. We found increased mRNA expression levels of the major SDF-1-cleaving proteases in whole BM cells from irradiated animals suggesting distinct spatial differences within the BM in which SDF-1 may play different autocrine and paracrine signaling roles beyond the immediate cell surface microenvironment.
    Tissue engineering. Part A. 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the effects of hyperglycemia and metformin (a popular biguanide antidiabetic) on periimplant healing. Thirty-six male rats were assigned to 3 groups: (1) nondiabetic Wistar-Kyoto rats (controls), (2) Goto-Kakizaki (GK) spontaneously diabetic rats (GK group), and (3) GK rats were fed metformin (100 mg/kg body weight per day) in their water for 4 weeks (GK + Met group). The right maxillary first molars were extracted and sites were allowed 1 month to heal. Titanium implants (1 × 3 mm) were placed in healed extraction sites. Six rats from each group were analyzed at weeks 1 and 4 by micro computed tomography for bone/implant contact ratio, percent bone volume, trabecular number, and bone mineral density. Blood was also analyzed for glucose, HbA1c, and pyridinoline (PYD). At week 1, glucose levels in the GK-Met rats were high, and all bone parameters were similar to GK rats (lower bone parameters and higher PYD than controls). At week 4, glucose levels in the GK-Met rats and all parameters were similar to controls. Hyperglycemic GK type 2 diabetic rats showed improved blood glucose and wound healing around oral implants after metformin administration.
    Implant dentistry 04/2014; · 1.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Long-term intravenous bisphosphonate therapy, especially zoledronate, has been linked to osteonecrosis of the jaw. Monthly injection of 4mg Zoledronate (Zomata) is a treatment for hypercalcemia of malignancy, multiple myeloma and metastatic bone lesions of solid tumors. A yearly injection of 5 mg Zoledronate (Reclast) is a treatment for osteoporosis in postmenopausal women. We analyzed the dose effect of zoledronate treatment on mandibular healing after dental extraction in an attempt to determine if a causal relationship exists between Zoledronate and ONJ. Methods: In the first experiment, 8 retired-breeder female Sprague Dawley rats were given two injections of 20μg/kg zoledronate, 4 weeks apart. The control group (n=8) received normal saline. At the time of the second injection, the 1st mandibular molar was extracted. In the second experiment, 20 animals received 13 weekly injections of either 80μg/kg (n=10) zoledronate or saline (n=10). On the day of the final administration, the 1st mandibular molar was extracted followed by the 2nd mandibular molar a week later. In both experiments, the animals were sacrificed 8 weeks following extraction for gross and Micro-CT evaluation. Results: With the smaller dose, 3 out of 8 (37.5%) rats in the zoledronate group had bone exposure versus none in the control group at 8 weeks. Decreased bone vitality was evident by microCT angiography. Preliminary results from the higher dose indicate that 100% of rats in the zoledronate group had bone exposure at 8 weeks, compared to 10% in the control group. Micro-CT showed sequestration of large bone segments from the alveolar process, but only in the high dose. Conclusion: Osteonecrosis of the jaw can be modeled in rats receiving zoledronate treatment, with dental extraction being the only co-morbidity. Rate and severity of osteonecrosis increase with increasing dose and duration of zoledronate treatment, suggesting a causal relationship.
    AADR Annual Meeting & Exhibition 2014; 03/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Long-term intravenous bisphosphonate therapy, especially zoledronate, has been linked to osteonecrosis of the jaw. The goal of this project is to test the hypothesis that the incidence and severity of osteonecrosis of the jaw (ONJ) increase with increasing amount of zoledronate delivered, regardless of the duration of treatment. Methods: In the first experiment, 8 retired-breeder female Sprague Dawley rats were given two injections of 20μg/kg zoledronate, 4 weeks apart. The control group (n=8) received normal saline. At the time of the second injection, the 1st mandibular molar was extracted. In the second experiment, 20 animals received 16 daily injections of either 150μg/kg zoledronate (n=10) or saline (n=10). On the day of the last injection, the 1st mandibular molar was extracted followed by extraction of the 2nd molar a week later. In both experiments, the animals were sacrificed 8 weeks following extraction for gross, histological and Micro-CT evaluation. Results: With the smaller dose, 3 out of 8 (37.5%) rats in the zoledronate group had some bone exposure versus none in the control group at 8 weeks. Decreased vitality of alveolar bone was confirmed with histology and Micro-CT angiography. Preliminary results from the higher dose indicate that 100% of the rats in the zoledronate group had bone exposure, as opposed to 0% in the control group. Micro-CT showed massive sequestration of the alveolar bone, but only in the high dose group. Conclusions: Osteonecrosis of the jaw can be modeled in rats receiving zoledronate treatment, with dental extraction being the only co-morbidity. Preliminary results suggest that the rate and severity of osteonecrosis increase with increasing dose of zoledronate treatment, even if the treatment was given over a shorter period.
    AADR Annual Meeting & Exhibition 2014; 03/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: A major problem in craniofacial surgery is non-healing bony defects. Causes of these defects range from blast wounds, post-operative tumor removal, generalized trauma and iatrogenic correction of craniofacial anomalies. There is no standard of care for these bony wounds, however, BMP-2 therapy is one option often utilized. Here we utilize inkjet-based biopatterning to investigate if low dose BMP-2 or TGFβ1 can be augmented by SDF1-β aimed at recruiting and homing immobilized endogenous stem cells in a calvarial defect model. Method: We utilized the C57BL6 mouse strain to test growth factors biopatterned on DermaMatrixTM delivery scaffolds. Briefly, we implanted nanogram-level doses of BMP2, TGFβ, SDF1β, BMP2+SDF1β, and TGFβ1+SDF1β biopatterned constructs and non-printed controls (matrix only) into 5 mm calvarial defects. At 4 weeks post-op, animals were sacrificed and the calvaria were harvested for uCT and faxitron analysis. We performed in vitro studies to determine the biochemical effects of these treatments on mouse calvarial cells. Result: Results suggest BMP2+SDF1 has slightly greater healing than BMP2 but significantly greater healing than TGFβ or TGFβ+SDF1β (p<0.05). Our cell data showed after 7 days in culture SDF1β (in the absence of BMP2) or with BMP2 increases in vitro markers of osteogenesis. Interestingly, there is a seemingly opposite effect for TGFβ1 and SDF1β, where their combination greatly down-regulates RUNX2. SDF1β augments osteogenesis in combination with BMP2 at 14 and 21 days in culture as well. Conclusion: These data indicate that a low dose growth factor therapy delivered using the biopatterning technology can aid in healing critical size injuries. SDF1β augments the ability for BMP2 to drive healing, a result confirmed in vivo and in vitro; however, because SDF-1β is detrimental to TGFβ-driven osteogenesis, its' effect on osteogenesis is not universal.
    AADR Annual Meeting & Exhibition 2014; 03/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The incidence of craniosynostosis occurs 1 in every 2500 births. The gene-environment interaction model suggests that genetic predispositions combined with certain environmental exposures can have additive or even multiplicative resulting in severely abnormal phenotypes. Based on Human epidemiological data the use of Vitamin B12 during pregnancy has a positive association with craniosynostosis (Carmichael et al., 2010). Here we aim to investigate the biochemical effects of exogenous exposure B12 on murine derived calvarial pre-osteoblasts. Method: We performed proliferation and quantitative alkaline phosphatase expression bioassays for murine derived MC3T3-E1 calvarial cells after B12 treatment at doses ranging from 10^-4 mol/liter to 10^-10 mol/liter for 3 and 7 days in culture. Result: B12 exposure led to increased proliferation (cell division or mitochondrial activity) especially after 7 days of treatment, t=7.100, p<0.001 in a dose dependent manner with our highest dose leading to the greatest increase, p=0.028. For qALP (differentiation) assay we observed an overall significant increase t=7.874, p<0.001 for the cells exposed to B12, the greatest effect occurring after 3 days in culture, F=39.371, p<0.001. There was also a significant difference by dose, F=8.541, P<0.001, the highest doses elicited the greatest increase in quantitative ALP. Conclusion: Exposure of B12 to calvarial derived cells increased both proliferation and differentiation suggesting the vitamin to be able to modify osteoblastogenesis. Thus, it is possible B12 exposure can effect cranial suture formation and an increase in osteogenesis could lead to premature suture fusion, craniosynostosis. Further studies will be performed to assess the effect of B12 on RNA expression of osteogenic genes (RUNX2, ALP, and OCN) in 3 and 7 day assays.
    AADR Annual Meeting & Exhibition 2014; 03/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The goal of our study was to investigate the effects of caffeine on differentiation and proliferation of mouse calvarial pre-osteoblasts. A positive relationship may suggest a link between maternal caffeine intake and craniosynostosis (premature neurocranial suture fusion) in the offspring. The incidence of craniosynostosis is 1 in every 2500 births. A positive correlation between caffeine use during pregnancy and craniosynostosis in the progeny has been demonstrated in epidemiological studies (1.34 OR, Browne et al., 2011). The positive correlation is seen at an intake of 300mg of caffeine a day or greater, which is equivalent to three cups of coffee. Our study aims to elucidate this relationship at a biochemical level. Method: We conducted proliferation and quantitative alkaline phosphatase expression bioassays for caffeine treatment at doses ranging from 10^-4 mol/liter to 10^-10 mol/liter for 3 and 7 day assays. Result: For proliferation, mean values compared to baseline proliferation media treatment suggest an increase in proliferation especially after 7 days of treatment, t=5.685, p<0.001. There were no significant differences for day by dose, day or dose after caffeine treatment. For qALP mean values compared to baseline media only treatment there were no significant changes overall t=1.465, p=0.152. However, data appears to show a relationship where there is a slight increase in ALP activity after 3 days but then a great decrease by 7 days after treatment with caffeine, p<0.05. Conclusion: Caffeine increases the proliferation of the pre-osteoblasts; however, it shows little effect on differentiation to mature osteoblasts. Caffeine may play a role in craniosynostosis due to increased osteoblast proliferation, but it is unlikely that it is a direct cause of craniosynostosis. Further studies will be performed to assess the effect of caffeine on RNA expression of osteogenic genes (RUNX2, ALP, and OCN) in 3 and 7 day assays.
    AADR Annual Meeting & Exhibition 2014; 03/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: In humans, mutations in TWIST1 result in Saethre-Chotzen syndrome (SCS), a genetic condition in humans characterized by craniosynostosis, digit malformations and occasional dental anomalies. Although Twist1 mutant mice share many of the same features observed in (SCS), a comprehensive description of the craniofacial and dental phenotype is lacking. The goal of this study is to test the hypothesis that haploinsufficiency of Twist1 results in altered tooth shape in mice. Method: MicroCT scans were obtained on 57 mice (16 Twist +/- mutants and 41 C57 wild types) at age P15. On each scan, the right mandibular molar was isolated and 13 3D landmarks were identified on the occlusal tooth surface. A geometric morphometric analysis was performed on the landmark coordinate data to quantify shape variation in the sample and statistically compare molar shape between the two mouse groups. Result: Statistically significant group differences in mean molar shape was observed (Procustes distance = 0.0327; p-value = 0.0030). Compared with wild-type mice, Twist mutant molars displayed major changes in the overall shape of the tooth, with the two mesial-most cusps converging on the midline to create a triangular, pointed appearance at the anterior end of the tooth when the occlusal surface was viewed from above. In contrast, the mesial portion of the wild-type molar was squarer in shape, giving the tooth an overall trapezoidal appearance. The position and orientation of cusps – particularly on the buccal side of the tooth – also differed between the two groups. Conclusion: Heterozygous Twist1 mutant mice clearly showed altered occlusal morphology on the first mandibular molar compared to wild types at age P15. This confirms prior clinical reports of altered tooth structure in Saethre-Chotzen syndrome and the role of Twist1 as an important modulator of dental morphogenesis.
    AADR Annual Meeting & Exhibition 2014; 03/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Human epidemiological data suggest that Selective Serotonin Reuptake Inhibitors (SSRI) have a positive association with craniosynostosis (2.4 OR, Alwain et al, 2007). Craniosynostosis (CS) is the premature fusion of one or more of the fibrous joints of the skull, which normally allow for the growth of the expanding neurocranium. The etiology of CS, whether genetic or environmental, is unknown for the majority of clinical cases. This study investigated the direct effects of Fluoxetine (Prozac) an SSRI on the biochemical pathway leading to proliferation and differentiation of murine derived calvarial pre-osteoblasts. Method: Proliferation and quantitative alkaline phosphatase expression (qALP) bioassays were performed on MC3T3-E1 mouse calvarial derived cells treated with Fluoxetine at doses ranging from 10^-4 mol/liter to 10^-10 mol/liter for 3 and 7 days in culture. Result: For proliferation (cell division or mitochondrial activity), mean values compared to baseline proliferation media treatment only suggest an increase in proliferation after 3 days of treatment, t=4.765, p<0.001. For qALP (osteoblastic differentiation), mean values compared to baseline proliferation media treatment suggest a significant decrease ALP expression after treatment t=4.302, p<0.001 after 7 days of treatment. Conclusion: Thus, it appears that SSRIs may have an effect on osteogenesis. Specifically, the results suggest an increase in cell proliferation and a decrease in osteoblastic activity. This pre-clinical data suggests an interaction between SSRI drugs and osteogenesis in calvarial cells. Further studies will be performed to assess the effect of Fluoxetine on RNA expression of osteogenic genes (RUNX2, ALP, and OCN) in 3 and 7 day assays.
    AADR Annual Meeting & Exhibition 2014; 03/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To compare in-vitro peak temperature rise during removal of a fractured abutment screw segment placed in a porcine mandible when using two commonly used drilling speeds: 600 or 2000 RPM. Method: Twenty 4.3 x 13 mm implants (Nobel Replace Tapered, Nobel Biocare, Yorba Linda, CA) were placed in ten dissected porcine mandibles (two implants per mandible). Localized defects were created in twenty surface-treated abutment screws (Nobel Biocare, Yorba Linda, CA), which were then torqued into each implant until screw fracture occurred. Three Type-K thermocouples (Omega Engineering, Stamford, CT) were inserted into bone at 3 mm (crest), 6 mm (body) and 9 mm (apical) depths from the implant platform, extending through the buccal bone to contact the implant surface. The fractured screws were removed utilizing a handpiece removal kit (Broken Screw Extractor Kit, Rhein83, New Rochelle, NY) using either 600 or 2000 RPM. Real-time temperature data were obtained at the three locations, and peak temperature values were recorded. A 2-way ANOVA was performed, using Tukey’s post-hoc test at a pre-set alpha of 0.05. Result: Mean temperatures were significantly higher using 2000 rpm than 600 RPM at the body (p < 0.001) and crest (p = 0.003), but not the apex (p = 0.225). No statistical differences in peak temperature were found among the three locations using 600 RPM (p = 0.179). In the 2000 RPM group, peak temperature at the body was consistently higher than that at the apex (p < 0.001), and more instances of temperature rise above 56˚ and 60˚ were observed. In one implant from this group, peak temperature exceeded the bone-damage threshold (50o for 30 sec). Conclusion: Removal of fractured abutment screw segments should be performed using low speed (600 rpm) rather than at 2000 rpm, to minimize temperature rise in adjacent bone.
    AADR Annual Meeting & Exhibition 2014; 03/2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Craniosynostosis (CS) is a relatively common birth defect resulting from the premature fusion of one or more cranial sutures. Human genetic studies have identified several genes in association with CS. One such gene that has been implicated in both syndromic (Saethre-Chotzen syndrome) and nonsyndromic forms of CS in humans is TWIST1. In this study, a heterozygous Twist1 knock out (Twist1(+/-) ) mouse model was used to study the craniofacial shape changes associated with the partial loss of function. A geometric morphometric approach was used to analyze landmark data derived from microcomputed tomography scans to compare craniofacial shape between 17 Twist1(+/-) mice and 26 of their Twist1(+/+) (wild type) littermate controls at 15 days of age. The results show that despite the purported wide variation in synostotic severity, Twist1(+/-) mice have a consistent pattern of craniofacial dysmorphology affecting all major regions of the skull. Similar to Saethre-Chotzen, the calvarium is acrocephalic and wide with an overall brachycephalic shape. Mutant mice also exhibited a shortened cranial base and a wider and shorted face, consistent with coronal CS associated phenotypes. The results suggest that these differences are at least partially the direct result of the Twist1 haploinsufficiency on the developing craniofacial skeleton. This study provides a quantitative phenotype complement to the developmental and molecular genetic research previously done on Twist1. These results can be used to generate further hypotheses about the effect of Twist1 and premature suture fusion on the entire craniofacial skeleton. Anat Rec, 2014. © 2014 Wiley Periodicals, Inc.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 03/2014; · 1.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone transport distraction osteogenesis (BTDO) is a surgical procedure that has been used over the last 30 years for the correction of segmental defects produced mainly by trauma and oncological resections. Application of BTDO has several clinical advantages over traditional surgical techniques. Over the past few years, several BTDO devices have been introduced to reconstruct mandibular bone defects. Based on the location and outline of the defect, each device requires a uniquely shaped reconstruction plate. To date, no biomechanical evaluations of mandibular BTDO devices have been reported in the literature. The present study evaluated the mechanical behavior of three different shaped prototypes of a novel mandibular bone transport reconstruction plate and its transport unit for the reconstruction of segmental bone defects of the mandible by using numerical models complemented with mechanical laboratory tests to characterize strength, fatigue, and stability. The strength test evaluated device failures under extreme loads and was complemented with optimization procedures to improve the biomechanical behavior of the devices. The responses of the prototypes were characterized to improve their design and identify weak and strong regions in order to avoid posterior device failure in clinical applications. Combinations of the numerical and mechanical laboratory results were used to compare and validate the models. In addition, the results remark the importance of reducing the number of animals used in experimental tests by increasing computational and in vitro trials.
    Journal of Medical Devices-Transactions of the Asme. 01/2014; 8(2).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background : A major problem in craniofacial surgery is non-healing bone defects. Autologous reconstruction remains the standard of care for these cases. Bone morphogenetic protein-2 (BMP-2) therapy has proven its clinical utility, although non-targeted adverse events occur due to the high milligram-level doses used. Ongoing efforts explore the use of different growth factors, cytokines, or chemokines, as well as co-therapy to augment healing. Methods : Here we utilize inkjet-based biopatterning to load acellular DermaMatrix delivery matrices with nanogram-level doses of BMP-2, stromal cell-derived factor-1β (SDF-1β), transforming growth factor-β1 (TGF-β1), or co-therapies thereof. We tested the hypothesis that bioprinted SDF-1β co-delivery enhances BMP-2 and TGF-β1-driven osteogenesis both in-vitro and in-vivo using a mouse calvarial critical size defect (CSD) model. Results : Our data showed that BMP-2 bioprinted in low-doses induced significant new bone formation by four weeks post-operation. TGF-β1 was less effective compared to BMP-2, and SDF-1β therapy did not enhance osteogenesis above control levels. However, co-delivery of BMP-2 + SDF-1β was shown to augment BMP-2-induced bone formation compared to BMP-2 alone. In contrast, co-delivery of TGF-β1 + SDF-1β decreased bone healing compared to TGF-β1 alone. This was further confirmed in vitro by osteogenic differentiation studies using MC3T3-E1 pre-osteoblasts. Conclusions : Our data indicates that sustained release delivery of a low-dose growth factor therapy using biopatterning technology can aid in healing CSD injuries. SDF-1β augments the ability for BMP-2 to drive healing, a result confirmed in vivo and in vitro; however, because SDF-1β is detrimental to TGF-β1-driven osteogenesis, its' effect on osteogenesis is not universal.
    Bone 01/2014; · 4.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence suggests that stromal cell-derived factor-1 (SDF-1/CXCL12) is involved in bone formation; though underlying molecular mechanisms remain to be fully elucidated. Also, contributions of SDF-1β, the second most abundant splice variant, as an osteogenic mediator remain obscure. We have shown that SDF-1β enhances osteogenesis by regulating bone morphogenetic protein-2 (BMP-2) signaling in vitro. Here we investigate the dose-dependent contribution of SDF-1β to suboptimal BMP-2-induced local bone formation, i.e. a dose that alone would be too low to significantly induce bone formation. We utilized a critical-size rat calvarial defect model and tested the hypotheses that SDF-1β potentiates BMP-2 osteoinduction and that blocking SDF-1 signaling reduces the osteogenic potential of BMP-2 in vivo. In preliminary studies, radiographic analysis at 4 weeks post-surgery revealed a dose-dependent relationship in BMP-2-induced new bone formation. We then found that co-delivery of SDF-1β potentiates suboptimal BMP-2 (0.5 µg) osteoinduction in a dose-dependent order, reaching comparable levels to the optimal BMP-2 dose (5.0 µg) without apparent adverse effects. Blocking the CXC receptor 4 (CXCR4)/SDF-1 signaling axis using AMD3100 attenuated the osteoinductive potential of the optimal BMP-2 dose, confirmed by qualitative histologic analysis. In conclusion, SDF-1β provides potent synergistic effects supporting BMP-induced local bone formation and thus appears a suitable candidate for optimization of bone augmentation using significantly lower amounts of BMP-2 in spine, orthopaedic, and craniofacial settings.
    Tissue Engineering Part A 12/2013; · 4.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Long-term use of intravenous bisphosphonates, such as zoledronic acid (zoledronate), has been linked to bisphosphonate-related osteonecrosis of the jaw (BRONJ). Invasive dental surgery seems to trigger the bone necrosis in most cases. Purpose: To determine the effects of zoledronic acid on the vascular structure of the rat mandible. Methods and Materials: Extracted of the mandibular first molar in rats that received two IV injections of zoledronate (20 µg/kg), 4 weeks apart. Zoledronate-treated rats (n=18) were then compared to a control group of untreated rats (n=18). At the 4th, 8th, and 12th week after molar extraction, eight rat mandibles from each group were perfused with 35% radiopaque triphenylbismuth in methyl methacrylate via carotid artery perfusion. Mandibles were harvested and examined by micro-CT to assess the spatial and dimensional changes of the vasculature as a result of zoledronate treatment. Results: The micro-CT analysis showed that zoledronic acid-treated rats had blood vessels that were thicker, less connected, and less ordered than control rats that were not exposed to zoledronic acid. Conclusions: This study demonstrated that treatment with zoledronic acid in rats is associated with vascular changes in alveolar bone. Further studies are underway to explore whether these vascular changes contribute to the pathogenesis of BRONJ.
    Journal of Oral Implantology 12/2013; · 1.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A number of studies have revealed that Type I diabetes (T1D) is associated with bone loss and an increased risk of fractures. T1D induces oxidative stress in various tissues and organs. Vitamin C plays an important role in the attenuation of oxidative stress; however, little is known about the effect of T1D induced oxidative stress on the regulation of vitamin C transporter in bone and bone marrow cells. To investigate this, T1D was induced in mice by multiple low dose injections of streptozotocin. We have demonstrated that endogenous antioxidants, glutathione peroxidase (GPx) and superoxide dismutase (SOD) are down-regulated in the bone and bone marrow of T1D. The vitamin C transporter isoform SVCT2, the only known transporter expressed in bone and bone marrow stromal cells (BMSCs), is negatively regulated in the bone and bone marrow of T1D. The μCT imaging of the bone showed significantly lower bone quality in the 8week T1D mouse. The in-vitro study in BMSCS showed that the knockdown of SVCT2 transporter decreases ascorbic acid (AA) uptake, and increases oxidative stress. The significant reversing effect of antioxidant vitamin C is only possible in control cells, not in knockdown cells. This study suggested that T1D induces oxidative stress and decreases SVCT2 expression in the bone and bone marrow environment. Furthermore, this study confirms that T1D increases bone resorption, decreases bone formation and changes the microstructure of bones. This study has provided evidence that the regulation of the SVCT2 transporter plays an important role not only in T1D osteoporosis but also in other oxidative stress-related musculoskeletal complications.
    Experimental and Molecular Pathology 08/2013; · 2.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Mice were injected weekly (20 mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+7%) and increased muscle fiber diameter of the extensor digitorum longus (+16%) and soleus (+6%) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone.
    Experimental gerontology 07/2013; · 3.34 Impact Factor

Publication Stats

123 Citations
78.06 Total Impact Points

Institutions

  • 2013–2014
    • Georgia Regents University
      Augusta, Georgia, United States
  • 2011
    • Mercer University
      • Division of Basic Medical Sciences
      Atlanta, Michigan, United States
  • 2007–2011
    • Baylor College of Dentistry
      • Department of Biomedical Sciences
      Dallas, Texas, United States
  • 2007–2010
    • Georgia Health Sciences University
      • • Department of Orthopaedic Surgery
      • • Department of Oral Biology
      • • Division of Oral and Maxillofacial Pathology
      Augusta, GA, United States
  • 2009
    • Universidad EAFIT
      • Department of Mechanical Engineering
      Medellín, Departamento de Antioquia, Colombia