Chronic treatment with zoledronic acid increases inflammatory markers in periodontium of rats

Silva, Paulo Goberlânio de Barros; Ferreira, Antonio Ernando Carlos; Oliveira, Carol; Brizeno, Luiz André Cavalcante; Wong, Deysi Viviana Tenazoa; Júnior, Roberto César Pereira Lima; Sousa, Fabrício Bitú; Mota, Mário Rogério Lima; Alves, Ana Paula Negreiros Nunes

doi:10.1111/jop.12640

Cited by 12 publications

(6 citation statements)

References 26 publications

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“…A previous study demonstrated elevated cytokine expression levels in patients presenting with MRONJ following BP treatment with the greatest increase in IL1β expression [ 66 ]. Similarly, the pro-inflammatory potential was increased after zoledronic acid treatment in an animal model [ 67 ]. TNFα, IL1β and IL8 are amongst the osteoclastogenic cytokines that promote bone resorption [ 68 ], while TNFα and IL1 inhibit osteoblast differentiation and collagen synthesis [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Bevacizumab and sunitinib mediate osteogenic and pro-inflammatory molecular changes in primary human alveolar osteoblasts in vitro

et al. 2022

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Antiangiogenic medications target the de novo blood vessel formation in tumorigenesis. However, these novel drugs have been linked to the onset of medication-related osteonecrosis of the jaw (MRONJ). The aim of this in vitro study was to examine the effects of the vascular endothelial growth factor A (VEGFA) antibody bevacizumab (BEV) and the receptor tyrosine kinase inhibitor (RTKI) sunitinib (SUN) on primary human osteoblasts derived from the alveolar bone. Primary human alveolar osteoblasts (HAOBs) were treated with BEV or SUN for 48 h. Cellular metabolic activity was examined by XTT assay. Differentially regulated genes were identified by screening of 22 selected osteogenic and angiogenic markers by quantitative real-time reverse transcriptase polymerase chain reaction (qRT2-PCR). Protein levels of alkaline phosphatase (ALP), collagen type 1, α1 (COL1A1) and secreted protein acidic and cysteine rich (SPARC) were examined by enzyme-linked immunoassay (ELISA). Treatment with BEV and SUN did not exhibit direct cytotoxic effects in HAOBs as confirmed by XTT assay. Of the 22 genes examined by qRT2-PCR, four genes were significantly regulated after BEV treatment and eight genes in the SUN group as compared to the control group. Gene expression levels of ALPL, COL1A1 and SPARC were significantly downregulated by both drugs. Further analysis by ELISA indicated the downregulation of protein levels of ALP, COL1A1 and SPARC in the BEV and SUN groups. The effects of BEV and SUN in HAOBs may be mediated by alterations to osteogenic and catabolic markers. Therapeutic or preventive strategies in MRONJ may address drug-induced depression of osteoblast differentiation.

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Section: Discussionmentioning

confidence: 99%

Bevacizumab and sunitinib mediate osteogenic and pro-inflammatory molecular changes in primary human alveolar osteoblasts in vitro

et al. 2022

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“…Similarly, inhibitory effects of BIS against neurogenic inflammation have also been reported [20]. On the other hand, an acute phase response (< 3 days) was induced by different BISs including ZOL with increased TNF-alpha release in patients [32], but tissue accumulation of PMNs, increased TNF-alpha release and marked oxidative stress were also demonstrated in other tissues, such as the gingiva [33] and the liver [34] in animal models. Furthermore, priming of immunological reactions was also attributed to ZOL [35].…”

Section: Discussionmentioning

confidence: 89%

Microcirculatory consequences of limb ischemia/reperfusion in ovariectomized rats treated with zoledronic acid

et al. 2019

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Background Nitrogen-containing bisphosphonates (BIS) are potent therapeutics in osteoporosis, but their use may result in osteonecrotic side-effects in the maxillofacial region. Periosteal microcirculatory reactions may contribute to the development of bone-healing complications, particularly in osteoporotic bones, where ischemia–reperfusion (IR) events often develop during orthopaedic/trauma interventions. The effect of BIS on the inflammatory reactions of appendicular long bones has not yet been evaluated; thus, we aimed to examine the influence of chronic zoledronate (ZOL) administration on the periosteal microcirculatory consequences of hindlimb IR in osteopenic rats. Materials and methods Twelve-week-old female Sprague–Dawley rats were ovariectomized (OVX) or sham-operated, and ZOL (80 μg/kg iv, weekly) or a vehicle was administered for 8 weeks, 4 weeks after the operation. At the end of the pre-treatment protocols, 60-min limb ischemia was induced, followed by 180-min reperfusion. Leukocyte-endothelial interactions were quantitated in tibial periosteal postcapillary venules by intravital fluorescence videomicroscopy. CD11b expression of circulating polymorphonuclear leukocytes (PMN, flow cytometry) and plasma TNF-alpha levels (ELISA) were also determined. Two-way RM ANOVA followed by the Holm–Sidak and Dunn tests was used to assess differences within and between groups, respectively. Results Limb IR induced significant increases in PMN rolling and firm adhesion in sham-operated and OVX rats, which were exacerbated temporarily in the first 60 min of reperfusion by a ZOL treatment regimen. Postischemic TNF-alpha values showed a similar level of postischemic elevations in all groups, whereas CD11b expression only increased in rats not treated with ZOL. Conclusions The present data do not show substantial postischemic periosteal microcirculatory complications after chronic ZOL treatment either in sham-operated or OVX rats. The unaltered extent of limb IR-induced local periosteal microcirculatory reactions in the presence of reduced CD11b adhesion molecule expression on circulating PMNs, however, may be attributable to local endothelial injury/activation caused by ZOL.

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“…Yet, at 3 h and 6 h, significantly increased expression levels of IL-1β, IL-6, and IL-8 were detected in the ZA-100 group. An in-vivo study proved that long-term ZA treatment would elevate the expression levels of pro-inflammatory cytokines (TNF-α and IL-1β) in the gingiva of rats ( de Barros Silva et al., 2017 ). However, in our study, after long-term ZA administration, the in-vivo results showed no significant difference in IL-1β levels between the control and experimental groups on days 3 and 7, while the experimental group had significantly higher expression levels of IL-1β at day 14 than the control group.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid affects the process of Porphyromonas gingivalis infecting oral mucosal epithelial barrier: An in-vivo and in-vitro study

Sun

Kong

et al. 2023

Front. Cell. Infect. Microbiol.

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Zoledronic acid (ZA), one of the commonly used bisphosphonates, is mainly used for bone-metabolic diseases. Studies proved that ZA has adverse effects on oral soft tissues. As the first line of innate immunity, the gingival epithelium could be infected by periodontal pathogens, which is a key process of the initiation of periodontal diseases. Yet, how ZA affects the periodontal pathogens infecting the epithelial barrier remains unclear. This study aimed to investigate the influences of ZA on the process of Porphyromonas gingivalis (P. gingivalis) infecting the gingival epithelial barrier via in-vitro and in-vivo experiments. In the in-vitro experiments, under the condition of different concentrations of ZA (0, 1, 10, and 100 μM), P. gingivalis was used to infect human gingival epithelial cells (HGECs). The infections were detected by transmission electron microscope and confocal laser scanning microscope. Besides, the internalization assay was applied to quantify the P. gingivalis, which infected the HGECs, in the different groups. To evaluate the expression levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and IL-8, by infected HGECs, real-time quantitative reverse transcription-polymerase chain reactions were applied. In the in-vivo experiments, rats were given ZA solution (ZA group) or saline (control group) by tail intravenous injection for 8 weeks. Subsequently, we put ligatures around the maxillary second molars of all the rats and inoculated P. gingivalis to the gingiva every other day from day 1 to day 13. The rats were sacrificed on days 3, 7, and 14 for micro-CT and histological analyses. The in-vitro results manifested that the quantity of P. gingivalis that had infected HGECs increased with the ZA concentrations. Pro-inflammatory cytokines expression by HGECs were significantly increased by 100 μM ZA. In the in-vivo study, compared to the control group, more P. gingivalis was detected in the superficial layer of gingival epithelium in the ZA group. Besides, ZA significantly increased the expression level of IL-1β on day 14 and IL-6 on days 7 and 14 in gingival tissues. These findings suggest that the oral epithelial tissues of patients who receive high-dose ZA treatment may be more susceptible to periodontal infections, resulting in severe inflammatory conditions.

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Chronic treatment with zoledronic acid increases inflammatory markers in periodontium of rats

Abstract: Chronic treatment with ZA increase proinflammatory cytokines and the number of inflammatory cells in periodontium of rats and GSH are expressed probably in a compensatory manner.

Cited by 12 publications

References 26 publications

Bevacizumab and sunitinib mediate osteogenic and pro-inflammatory molecular changes in primary human alveolar osteoblasts in vitro

Bevacizumab and sunitinib mediate osteogenic and pro-inflammatory molecular changes in primary human alveolar osteoblasts in vitro

Microcirculatory consequences of limb ischemia/reperfusion in ovariectomized rats treated with zoledronic acid

Zoledronic acid affects the process of Porphyromonas gingivalis infecting oral mucosal epithelial barrier: An in-vivo and in-vitro study

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