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Open AccessArticle

Structure-Dependent Effects of Bisphosphonates on Inflammatory Responses in Cultured Neonatal Mouse Calvaria

1
Department of Dental Pharmacology, School of Dentistry, Showa University, Tokyo 142-8555, Japan
2
Department of Molecular Cell Pharmacology, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan
3
Center for Environmental Dentistry, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan
4
Department of Dental Pharmacology, School of Dentistry, Ohu University, Fukushima 963-8611, Japan
5
Division of Oral Physiology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
6
Division of Craniofacial Anomalies, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
*
Author to whom correspondence should be addressed.
Antioxidants 2020, 9(6), 503; https://doi.org/10.3390/antiox9060503
Received: 3 April 2020 / Revised: 3 June 2020 / Accepted: 4 June 2020 / Published: 9 June 2020
(This article belongs to the Special Issue Feature Papers in Antioxidants in 2020)
Bisphosphonates (BPs) are classified into two groups, according to their side chain structures, as nitrogen-containing BPs (NBPs) and non-nitrogen-containing BPs (non-NBPs). In this study, we examined the effects of NBPs and non-NBPs on inflammatory responses, by quantifying the inflammatory mediators, prostaglandin E2 (PGE2) and nitric oxide (NO), in cultured neonatal mouse calvaria. All examined NBPs (pamidronate, alendronate, incadronate, risedronate, zoledronate) stimulated lipopolysaccharide (LPS)-induced PGE2 and NO production by upregulating COX-2 and iNOS mRNA expression, whereas non-NBPs (etidronate, clodronate, tiludronate) suppressed PGE2 and NO production, by downregulating gene expression. Additionally, [4-(methylthio) phenylthio] methane bisphosphonate (MPMBP), a novel non-NBP with an antioxidant methylthio phenylthio group in its side chain, exhibited the most potent anti-inflammatory activity among non-NBPs. Furthermore, results of immunohistochemistry showed that the nuclear translocation of NF-κB/p65 and tyrosine nitration of cytoplasmic protein were stimulated by zoledronate, while MPMBP inhibited these phenomena, by acting as a superoxide anion (O2) scavenger. These findings indicate that MPMBP can act as an efficacious agent that causes fewer adverse effects in patients with inflammatory bone diseases, including periodontitis and rheumatoid arthritis. View Full-Text
Keywords: bisphosphonate; antioxidant; anti-inflammatory; PGE2; NO; peroxynitrite; NF-κB; nitrotyrosine; bisphosphonate-related osteonecrosis of the jaw (BRONJ); periodontitis bisphosphonate; antioxidant; anti-inflammatory; PGE2; NO; peroxynitrite; NF-κB; nitrotyrosine; bisphosphonate-related osteonecrosis of the jaw (BRONJ); periodontitis
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Suzuki, K.; Takeyama, S.; Murakami, S.; Nagaoka, M.; Chiba, M.; Igarashi, K.; Shinoda, H. Structure-Dependent Effects of Bisphosphonates on Inflammatory Responses in Cultured Neonatal Mouse Calvaria. Antioxidants 2020, 9, 503.

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