Abstract
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.
Highlights
Bisphosphonates (BPs) are well recognized as potent inhibitors of osteoclastic bone resorption and have been successfully used for the treatment of various metabolic bone diseases, such as osteoporosis, Paget’s disease, hypercalcemia, and osteolytic tumor-induced bone diseases, which cause excessive bone resorption [1]
In previous studies focusing on the structure–activity relationships among various BPs, we found that MPMBP possessed several unique functions that could not be observed in nitrogen-containing BPs (NBPs), such as (i) inhibition of superoxide anion (O2 − ) generation in human polymorphonuclear leukocytes (PMN) [13], (ii) prevention against mouse collagen-induced arthritis [14] and rat adjuvant arthritis [15,16], characterized by persistent inflammation in the joints [17], and (iii) prevention against inflammatory alveolar bone loss in experimental periodontitis [18]
Since one of the major causes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is persistent inflammation induced by host defense against bacterial infections in the oral cavity, we first explored whether NBPs and non-NBPs have
Summary
Bisphosphonates (BPs) are well recognized as potent inhibitors of osteoclastic bone resorption and have been successfully used for the treatment of various metabolic bone diseases, such as osteoporosis, Paget’s disease, hypercalcemia, and osteolytic tumor-induced bone diseases, which cause excessive bone resorption [1]. Antioxidants 2020, 9, 503 activity [3]) Their pharmacological characteristics, including potency of anti-resorption activity, mechanism of action, and adverse effects vary considerably, depending on their side chain structures. With regard to osteoclast inactivation, NBPs have been reported to inhibit farnesyl pyrophosphate synthase in the mevalonate pathway in osteoclasts [4], thereby preventing the prenylation of small G proteins required for osteoclast function, while non-NBPs form cytotoxic metabolites that compete with ATP in energy metabolism. Both of these can cause apoptosis in osteoclasts [5]. Among the adverse effects of BPs, the incidence of bisphosphonate-related osteonecrosis of the jaw (BRONJ), characterized by an exposed necrotic jaw bone [6] filled with bacterial aggregates, has been reported to be much higher in patients receiving long-term and/or high-dose intravenous
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