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    Alendronate decreases contractile responses by affecting ATP-sensitive potassium channels in human left internal mammary artery rings
    (Asian Network for Scientific Information, 2014) Arun M.Z.; Reel B.; Guzeloglu M.; Albayrak G.; Aykut K.; Hazan E.
    Bisphosphonates, including alendronate, are widely used for the treatment of osteoporosis, hypercalcemia and bone metastasis associated with cancer. However, recent evidence has demonstrated anti-atherosclerotic effects of bisphosphonates in animal models and atherosclerotic patients. Besides, some studies have shown that bisphosphonates change calciwn homeostasis in cardiomyocytes and interfere L-type calciwn chmels in vascular smooth muscle cells. Therefore, in the present study it was aimed to investigate the effects of alendronate on contractile responses and ATP-sensitive potassiwn channels in vitro in hwnan Left Internal Mammary Artery (LIMA). Hwnan LIMA rings were placed into isolated organ chambers. After resting period, rings were kept for an hour in incubation mediwn which contains alendronate (10-6 M) or not (control) and responses of the rings to the contractile agents were examined. The incubation of two rings was performed in the presence of glibenclamide which is ATP-sensitive potassiwn channel blocker (10-6M). Maximwn contractile responses of LIMA rings to noradrenalin and serotonin decreased in the presence of alendronate. In concomitant incubation of LIMA with alendronate and glibenclamide reversed decreased contractions to noradrenalin or serotonin caused by alendronate. However, neither alendronate nor glibenclamide changed sensitivity to noradrenaline or serotonin. The present findings point out that alendronate may change intracellular calciwn dynamics in hwnan LIMA, due to the activation of ATP-sensitive potassiwn channels which have an important role on cardiovascular system. © 2014 Asian Network for Scientific Information
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    Analysis of tumor necrosis factor ?-induced and nuclear factor ?B-silenced LNCap prostate cancer cells by RT-qPCR
    (Spandidos Publications, 2014) Gonen-Korkmaz C.; Sevin G.; Gokce G.; Arun M.Z.; Yildirim G.; Reel B.; Kaymak A.; Ogut D.
    Prostate cancer is the second leading cause of morbidity and mortality in males in the Western world. In the present study, LNCaP, which is an androgen receptor-positive and androgen-responsive prostate cancer cell line derived from lymph node metastasis, and DU145, which is an androgen receptor-negative prostate cancer cell line derived from brain metastasis, were investigated. TNF? treatment decreased p105 and p50 expression and R1881 treatment slightly decreased p105 expression but increased p50 expression with or without TNF? induction. As an aggressive prostate cancer cell line, DU145 transfected with six transmembrane protein of prostate (STAMP)1 or STAMP2 was also exposed to TNF?. Western blotting indicated that transfection with either STAMP gene caused a significant increase in NF?B expression following TNF? induction. In addition, following the treatment of LNCaP cells with TNF?, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed with a panel of apoptosis-related gene primers. The apoptosis-related genes p53, p73, caspase 7 and caspase 9 showed statistically significant increases in expression levels while the expression levels of MDM2 and STAMP1 decreased following TNF? induction. Furthermore, LNCaP cells were transfected with a small interfering NF?B (siNF?B) construct for 1 and 4 days and induced with TNF? for the final 24 h. RT-qPCR amplifications were performed with apoptosis-related gene primers, including p53, caspases and STAMPs. However, no changes in the level of STAMP2 were observed between cells in the presence or absence of TNF? induction or between those transfected or not transfected with siNF?B; however, the level of STAMP1 was significantly decreased by TNF? induction, and significantly increased with siNF?B transfection. Silencing of the survival gene NF?B caused anti-apoptotic STAMP1 expression to increase, which repressed p53, together with MDM2. NF?B silencing had varying effects on a panel of cancer regulatory genes. Therefore, the effective inhibition of NF?B may be critical in providing a targeted pathway for prostate cancer prevention. © 2014, Spandidos Publications. All right reserved.
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    Diverse patterns of cyclooxygenase-independent metalloproteinase gene regulation in human monocytes
    (2011) Reel B.; Sala-Newby G.B.; Huang W.-C.; Newby A.C.
    BACKGROUND AND PURPOSE Matrix metalloproteinase (MMP) production from monocyte/macrophages is implicated in matrix remodelling and modulation of inflammation. However, knowledge of the patterns and mechanisms of gene regulation of MMPs and their endogenous tissue inhibitors (TIMPs) is fragmentary. MMP up-regulation may be a target for cyclooxygenase (COX) and prostaglandin (PG) receptor inhibition, but the extent and mechanisms of COX-independent MMP up-regulation are unclear. EXPERIMENTAL APPROACH We studied MMP mRNA expression and selected protein levels in human peripheral blood monocytes before and after adhesion, upon stimulation with bacterial lipopolysaccharide (LPS), PGE 2 or forskolin and after culturing with monocyte colony-stimulating factor on plastic or human fibronectin for up to 7 days. KEY RESULTS Monocyte adherence for 2 h transiently up-regulated COX-2, MMP-1, MMP-7 and MMP-10 mRNAs, and persistently up-regulated MMP-2, MMP-9, MMP-14 and MMP-19 mRNAs. LPS, PGE 2 or forskolin selectively increased MMP-1, MMP-9, MMP-10, MMP-12 and MMP-14 mRNAs. LPS increased PGE 2 production through COX but up-regulated MMP levels independently of COX. Differential dependence on inhibition of p42/44 and p38 mitogen-activated protein kinases, c-jun N-terminal kinase and inhibitor of ?B kinase2 paralleled the diverse patterns of MMP stimulation by LPS. Differentiation on plastic increased mRNA levels of MMP-7, MMP-9, MMP-12 and MMP-14 and TIMP-2 and TIMP-3 independently of COX; fibronectin accelerated MMP but not TIMP up-regulation. CONCLUSIONS AND IMPLICATIONS Adhesion, LPS stimulation and maturation of human monocytes lead to selective, COX-independent MMP and TIMP gene regulation, which is a potential target for selective inhibition by signalling kinase inhibitors. © 2011 The British Pharmacological Society.
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    Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF-?b signalling in LPS-induced PC3 cells
    (Via Medica, 2016) Ogut D.; Reel B.; Korkmaz C.G.; Arun M.Z.; Micili S.C.; Ergur B.U.
    Introduction. Matrix metalloproteinase enzymes (MMPs) play important role in inflammation, malignant cell proliferation, invasion and angiogenesis by mediating extracellular matrix degradation. Doxycycline, a synthetic tetracycline, behaves as a MMP inhibitor at a subantimicrobial dose and inhibits tumor cell proliferation, invasion and angiogenesis. The aberrant activity of nuclear factor kappa B (NF-?B) causes activation of MMPs and thereby proliferation and invasion of cancer cells. The aim of this study was to investigate the effects of doxycycline on the expression of MMPs in lipopolysaccharide (LPS)-induced PC3 human prostate cancer cells and the possible role of NF-?B signaling. Material and methods. PC3 cells were incubated with LPS (0.5 µg/mL) for 24 h in the presence or absence of doxycycline (5 µg/mL). The effects of LPS and doxycycline on the expressions of MMP-2, MMP-8, MMP-9, MMP-10, NF-?B/p65, I?B-?, p-I?B-?, IKK-ß were examined by Western blotting and immunohistochemistry in PC3 cells. Furthermore, relative proteinase activities of MMP-2 and MMP-9 were determined by gelatin zymography. Results. LPS increased expression and activity of MMP-9 and expression of MMP-8, MMP-10, NF-?B/p65, p-I?B-?, IKK-ß and doxycycline down-regulated its effects with the exception of MMP-10 expression. The expression of MMP-2 and I?B-a was affected by neither LPS nor doxycycline. Conclusions. Our findings indicate that doxycycline inhibits the expression of various MMPs and NF-?B signaling may play a role in the regulation of MMPs expression in LPS-induced PC3 human prostate cancer cells. ©Polish Society for Histochemistry and Cytochemistry.
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    Effect of nifedipine on the collar-induced intimal thickening and vascular reactivity changes in rabbits
    (2005) Reel B.
    The positioning of a soft and nonocclusive silicon collar around the rabbit carotid artery induces intimal thickening and characteristic vascular reactivity changes. In the present study, we investigated whether the treatment with nifedipine, a dihydropyridine derivative calcium channel blocker (CCB) (40 mg/kg/day, p.o.), inhibit development of intimal thickening and accompanying vascular reactivity changes in this model. Neither intimal thickening nor vascular reactivity changes were effected by nifedipine treatment in this model.
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    The effects of PPAR-? agonist pioglitazone on renal ischemia/reperfusion injury in rats
    (2013) Reel B.; Guzeloglu M.; Bagriyanik A.; Atmaca S.; Aykut K.; Albayrak G.; Hazan E.
    Background: Acute renal failure due to renal ischemia/reperfusion (IR) injury is a significant clinical problem in cardiovascular surgery. Reactive oxygen species and inflammation play essential roles in the pathophysiology of IR injury. Matrix metalloproteinases (MMPs) are enzymes that play important roles in inflammation and mediate extracellular matrix degradation. It is known that peroxisome proliferator-activated receptor-? agonists have antiinflammatory and antioxidant effects. In the present study, we aimed to investigate the effects of pioglitazone, a synthetic peroxisome proliferator-activated receptor-? agonist, on MMPs and oxidative stress in a renal IR injury model in rats. Materials and methods: Male Wistar albino rats were divided into three groups: control (n = 7), placebo (n = 7; saline/p.o.), and pioglitazone (n = 7; 5 mg/kg/day/p.o.). In the control group, a right nephrectomy was conducted without left renal IR injury. In the placebo and pioglitazone groups, pretreatments were started 3 d before operation. In both groups, left renal pedicles were clamped for 60 min and then reperfused for 60 min. Paraffinized renal sections were evaluated histopathologically. Furthermore, expressions of MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2, superoxide dismutase 1 (SOD1), and p47-phox/p67-phox subunits of NADPH oxidase were determined by immunostaining and scoring. Results: In the placebo group, renal IR injury induced diffuse tubular necrosis and intense acute inflammation, but pioglitazone inhibited these effects. MMP-2, MMP-9, and TIMP-2 expression increased in the placebo group. However, while MMP-2 and -9 expression decreased, TIMP-2 expression did not change in the pioglitazone group. p47-phox/p67-phox expression increased in the placebo group, but SOD1 expression did not change. Pioglitazone diminished p47-phox/p67-phox expression, whereas it enhanced SOD1 expression. Conclusion: Our results suggest that pioglitazone might be helpful to reduce renal IR injury because of its antiinflammatory and antioxidant effects.
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    The effects of PPAR? agonist rosiglitazone on neointimal hyperplasia in rabbit carotid anastomosis model
    (2012) Guzeloglu M.; Reel B.; Atmaca S.; Bagriyanik A.; Hazan E.
    Background: Neointimal hyperplasia involving smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) degradation is an important component of atherosclerosis. It develops as a response to vascular injury after balloon angioplasty and vascular graft placement. Matrix metalloproteinases (MMPs) induce SMC proliferation, migration and contribute to intimal hyperplasia by degrading ECM. PPAR? agonists inhibit SMC proliferation, migration and lesion formation. In this study, we aimed to investigate the effects of PPAR? agonist rosiglitazone on neointimal hyperplasia and gelatinase (MMP-2 and MMP-9) expressions in rabbit carotid anastomosis model.Methods: New Zealand white rabbits (n = 13, 2.7-3.2 kg) were divided into placebo and treatment groups. Right carotid artery (CA) was transected and both ends were anastomosed. Treatment group (n = 6) received rosiglitazone (3 mg/kg/day/p.o.) and placebo group (n = 7) received PBS (phosphate buffered saline, 2.5 ml/kg/day/p.o.) for 4 weeks postoperatively. After the sacrification, right and left CAs were isolated. Morphometric analyses and immunohistochemical examinations for gelatinases were performed.Results: Intimal area (0.055 ± 0.005 control vs 0.291 ± 0.020 µm 2 anastomosed, p < 0,05) and index (0.117 ± 0.002 control vs 0.574 ± 0.013 anastomosed, p < 0,01) significantly increased in anastomosed arteries compared to control arteries from placebo group. However, in rosiglitazone-treated group, intimal area (0.291 ± 0.020 PBS vs 0.143 ± 0.027 rosiglitazone, p < 0,05) and index (0.574 ± 0.013 PBS vs 0.263 ± 0.0078 rosiglitazone, p < 0,01) significantly decreased. Furthermore, gelatinase immunopositivity was found to have significantly increased in anastomosed arteries from placebo group and decreased with rosiglitazone treatment.Conclusions: These results suggest that rosiglitazone may prevent neointimal hyperplasia, which is the most important factor involved in late graft failure, by inhibiting gelatinase enzyme expression. © 2012 Guzeloglu et al.; licensee BioMed Central Ltd.
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    The effects of zoledronic acid on neointimal hyperplasia: A rabbit carotid anastomosis model [Neointimal hiperplazi üzerine zoledronik asidin etkileri: Tavşan karotis anastomoz modeli]
    (2011) Güzeloglu M.; Gül M.; Reel B.; Yürekli I.; Aykut K.; Hazan E.
    Objective: The aim of the present study was to investigate the effect of zoledronic acid (ZA), as a matrix metalloproteinase inhibitor, on neointimal hyperplasia in rabbit carotid anastomosis model. Methods: New Zealand male rabbits were divided into two groups as placebo and treatment groups in this experimental study. After anesthesia, the right carotid artery of each rabbit was end-to-end anastomosed with an 8/0 polypropylene suture. Left carotid artery was kept as control without any operation. Placebo group (n=6) received phosphate buffered saline (PBS) (0.5mL/kg/day/s.c.) for 28 days postoperatively, whereas ZA group (n=6) received ZA (100 µg/kg/day/s.c.) for the same period. After sacrification, the anastomosed and control arteries were isolated. Morphometric and immunohistochemical examinations were performed. Statistical analyses of morphometric and immunohistochemical data were performed using two-way ANOVA and Chi-square test respectively. Results: In PBS group, vascular injury in the anastomosed artery significantly increased the intimal area (anastomosed: 112.51±61.18 µm 2*1000 vs. control: 22.62±4.26µm 2*1000, p<0.01) and intima/media index (anastomosed: 0.347±0.29 vs. control: 0.075±0.01, p<0.05) compared to control artery. ZA significantly reduced the intimal area (39.29±18.21 µm 2*1000, p<0.01) and intima/media index (0.112±0.07, p<0.05) compared to PBS group. Additionally, ?-smooth muscle actin immunopositivity was found significantly decreased in anastomosed arteries from ZA group (ZA: 2.33±0.52 vs. PBS: 3.50±0.5, p<0.05). Moreover, intensive gelatinase (MMP-2 and MMP-9) immunoreactivities were clearly seen in anastomosed arteries compared to control arteries from PBS group. ZA apparently decreased immunopositivities for gelatinases in anastomosed arteries. Conclusion: ZA might be a promising agent for prevention of neointimal hyperplasia, which is the most significant cause of graft failures in late postoperative period. © 2011 by AVES Yayi{dotless}nci{dotless}li{dotless}k Ltd.
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    Endothelin receptor-independent correlation between HSP47 and collagen in rabbit model of early atherosclerosis [tavşan erken ateroskleroz modelinde HSP47 ile kolajen arasmdaki endotelin reseptöründen bagimsiz i·lişki]
    (Turkiye Klinikleri, 2011) Reel B.; Çavdar Z.; Ergür B.U.; Özkal S.; Özşarlak-Sözer G.; Oktay G.; Kerry Z.
    Objective: Collagen in the extracellular matrix (ECM) plays an important role in modulation of response to the vascular injury during the progression of atherosclerosis and restenosis. Collagen can regulate smooth muscle cell (SMC) proliferation, migration and matrix metalloproteinase (MMP) production. Therefore, collagen turnover in the arteries is an important determinant of inti- mal thickening. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is thought to be essential for the processing and secretion of procollagen molecules. Endothelin (ET) is a strong chemoatractant and mitogen promoting SMC proliferation and migration. The aim of this study was to investigate the possible role of HSP47 and its relation to collagen synthesis, and the effects of a nonselective ETA/ETB receptor antagonist, TAK-044 in collar-induced early atherosclerosis model. Material and Methods: New Zealand white rabbits were divided into two groups. Both groups received vehicle (0.9% NaCl 0.8 ml/kg/day, s.c.) or TAK-044 (5 mg/kg/day, s.c.) for three weeks. On 8th day, a non-occlusive silicon collar was placed around the left carotid artery. The right carotid artery was sham-operated. HSP47 expression in carotid arteries were determined immunohistochemically. Furthermore, total collagen levels, collagen expression and type I procollagen expression were established. Results: HSP47 expression correlated with collagen expression did not change in collared arteries. TAK-044 treatment did not affect HSP47 and collagen levels. Conclusion: There was a correlation between HSP47 expression and collagen expression in carotid arteries. However, intimal thickening did not induce HSP47 expression and early collagen development. The ineffectivenes of TAK-044 suggests that ET-1 signaling may not be implicated in HSP47 and collagen in this model. © 2011 by Türkiye Klinikleri.
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    Erratum: Collar-induced changes in matrix metallo-proteinase-2 and -9 activities in the rabbit carotid artery and effect of endothelin antagonism (European Journal of Biochemistry (2004) 271, Suppl. 1 (83))
    (2004) Reel B.; Oktay G.; Tanriverdi S.; Çavdar Z.; Özşarlak Şözer G.; Işlekel H.; Kerry I.
    [No abstract available]
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    Matrix metalloproteinases and atherosclerosis: Review [Matriks metalloproteinaz enzimleri ve ateroskleroz]
    (Turkiye Klinikleri, 2006) Reel B.
    Matrix metalloproteinases (MMPs) are a family of Zn++- and Ca++-dependent neutral endopeptidases that degrade components of extracellular matrix (ECM). The activity of MMPs is essential for many of the processes involved in atherosclerotic plaque formation, such as infiltration of inflammatory cells, smooth muscle cell migration and proliferation. Furthermore, MMPs have also been implicated in events leading to plaque destabilization and rupture. The activity of MMPs is tightly controlled by endogen tissue inhibitors (Tissue inhibitors of metalloproteinases; TIMPs), under physiological conditions. However, during atherosclerotic plaque development, MMP activity is increased by rising cytokine- and growth factor-stimulating gene transcription, elevated zymogen activation and an imbalance in the MMP/TIMP ratio. It is therefore conceivable that inhibition of MMPs or re-establishing the MMP/TIMP balance may be useful in treating the symptoms of atherosclerosis. Recent studies demonstrated that synthethic MMP inhibitors were likely to be useful in treating the symptoms of atherosclerosis. The objective of this review was to assist the better understanding of the effects and contributions of MMPs on the pathogenesis of atherosclerosis. Understanding of the roles of MMPs in the pathogenesis of atherosclerosis may give rise to the proposition of new approaches for the treatment of life-threatening atherosclerotic disorders and to the development of new specific MMP inhibitors as pharmacological agents. Copyright © 2006 by Türkiye Klinikleri.
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    Nifedipine induces expansive vascular remodeling of carotid arteries in rabbit collar model [Nifedipin tavşan yaka modelinde karotid arterlerin dişa dogru vasküler yeniden modellenmesine yol açar]
    (Turkiye Klinikleri, 2011) Reel B.; Ergür B.U.
    Objective: Intimal thickening is an adaptive response to injury and to stimuli acting on the vessel wall. Vascular remodeling (VR) is defined as the changes in the size and/or composition of the vessels in response to dynamic and trophic stimuli. Inappropriate VR plays a crucial role in lumen loss and pathogenesis of cardiovascular diseases. Calcium channel blockers (CCBs) have been known to have vascular protective effects. However, the precise molecular mechanisms of these effects have not been fully elucidated. The aim of this study was to investigate the effects of nifedipine on intimal thickening and pathological VR, and to examine the role of the discoidin domain receptors (DDRs), which are collagen receptors, in the VR process in the collar model. Material and Methods: White rabbits were randomized into two groups. The groups received vehicle or nifedipine (40 mg/kg/day, p.o.) for three weeks. After seven days, a non-occlusive silicone collar was placed around the left carotid artery. To evaluate intimal thickening and VR, the intimal area, medial and luminal perimeters were measured. Furthermore, DDR expressions were assessed immunohistochemically. Results: Nifedipine did not inhibit intimal thickening. The collar provoked inward VR. Neither collagen content nor DDR expressions were affected by the collar. Nifedipine constituted hypertrophic outward expansive VR by involving luminal and arterial enlargement. However nifedipine did not change either collagen ingredient or DDR expressions. Conclusion: Ni- fedipine did not inhibit intimal thickening. However, it resulted in favorable expansive VR without changing collagen contents and DDR expressions. Thus, nifedipine may help to maintain luminal patency and to prevent restenosis after balloon angioplasty. © 2011 by Türkiye Klinikleri.
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    The role of endothelin receptor antagonism in collar-induced intimal thickening and vascular reactivity changes in rabbits
    (2005) Reel B.; Ozkal S.; Islekel H.; Ozer E.; Oktay G.; Sozer G.O.; Tanriverdi S.; Turkseven S.; Kerry Z.
    Intimal thickening, due to smooth muscle cell migration and proliferation, is considered to be one of the major components of vascular proliferative disorders such as atherosclerosis and restenosis. One experimental model, resulting in intimal thickening in the rabbit, involves placing a silicon collar around the carotid artery, and is used in this study. Endothelin is known to act as a strong mitogen and to stimulate smooth muscle cell proliferation and migration. We investigated the contribution of endothelin to the development of collar-induced intimal thickening and the effects of TAK-044, (5mg kg -1 daily, s.c), a non-selective ETA/ETB receptor antagonist, on intimal thickening and vascular reactivity changes in the collared rabbit carotid artery. Endothelin levels and the intimal cross-sectional area, as well as the ratio of intimal area to media (index), increased significantly in collared arteries as compared with those in sham-operated arteries. TAK-044 significantly inhibited intimal thickening and also decreased the index without affecting increased endothelin levels in collared arteries. Vascular reactivity changes in response to collaring produced predictable effects, such as decreased contractile responses to vasoconstrictor agents and increased sensitivity to serotonin (5-hydroxytryptamine, 5-HT). In terms of contractile responses in this model, TAK-044, in particular, did not affect collar-induced vascular reactivity changes. These results suggest that endothelin may be involved in the pathogenesis of collar-induced intimal thickening. As an endothelin receptor antagonist, TAK-044 may potentially be beneficial in the treatment of atherosclerosis. © 2005 The Authors.
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    Zoledronate upregulates MMP-9 and -13 in rat vascular smooth muscle cells by inducing oxidative stress
    (Dove Medical Press Ltd., 2016) Arun M.Z.; Reel B.; Sala-Newby G.B.; Bond M.; Tsaousi A.; Maskell P.; Newby A.C.
    Background: Bisphosphonates, including zoledronate, target osteoclasts and are widely used in the treatment of osteoporosis and other bone resorption diseases, despite side effects that include damaging the stomach epithelium. Beneficial and adverse effects on other organ systems, including the cardiovascular system, have also been described and could impact on the use of bisphosphonates as therapeutic agents. Vascular smooth muscle cells (VSMCs) are major constituents of the normal vascular wall and have a key role in intimal thickening and atherosclerosis, in part by secreting MMPs that remodel the extracellular matrix and cleave cell surface proteins or secreted mediators. In this study, we investigated the effects of zoledronate on MMP expression. Methods: Rat VSMCs were stimulated by PDGF (50 ng/mL) plus TNF-? (10 ng/mL) or left unstimulated for a further 24 hours in serum-free medium. In other series of experiments, cells were pre-treated either with SC-514 (50 µM) or with apocynin (20 nM) for 2 hours, then zoledronate (100 µM) was added into 2% fetal calf serum containing medium for 24 hours. Results and discussion: Using isolated rat VSMCs in culture, zoledronate (100 µM) increased MMP-9 and -13 mRNA expressions but inhibited MMP-2 expression. MMP-9 and MMP-13 up-regulation was shown to depend on the NF-?B pathway; and this was activated by zoledronate. Furthermore, zoledronate elevated the levels of reactive oxygen species detected by either dichlorofluorescein in isolated VSMCs or lucigenin enhanced chemiluminescence in rat aortic rings in vitro. Apocynin, an inhibitor of NADPH oxidase, reversed NF-?B activation and MMP-9 and MMP-13 up-regulation by zoledronate. Conclusion: We conclude that zoledronate increases MMP-9 and MMP-13 expressions in rat VSMCs dependent upon stimulation of the NF-?B pathway by reactive oxygen species. Effects on MMP expression may contribute to the pharmacologic profile of bisphosphonates. © 2016 Arun et al.