A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl− extrusion in osteoclasts

Ohgi, Kimiko; Kajiya, Hiroshi; Okamoto, Fujio; Nagaoka, Yoshiyuki; Onitsuka, Tokuya; Nagai, Atsushi; Sakagami, Ryuji; Okabe, Koji

doi:10.1007/s00210-013-0857-0

Cited by 8 publications

(3 citation statements)

References 43 publications

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“…Resorption of alveolar bones by osteoclasts is essential for tooth eruption 7 . The osteopetrosis patients caused by osteoclasts dysfunction usually presented impacted and malformed teeth and the involved genes include RANKL 15 16 , TCIRG1 17 , etc. ClC-7 is highly expressed in the ruffled membrane of osteoclasts, and responsible for acidifying resorption lacuna.…”

Section: Discussionmentioning

confidence: 99%

ClC-7 Deficiency Impairs Tooth Development and Eruption

Wang

Pan

et al. 2016

Sci Rep

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CLCN7 gene encodes the voltage gated chloride channel 7 (ClC-7) in humans. The mutations in CLCN7 have been associated with osteopetrosis in connection to the abnormal osteoclasts functions. Previously, we found that some osteopetrosis patients with CLCN7 mutations suffered from impacted teeth and root dysplasia. Here we set up two in vivo models under a normal or an osteoclast-poor environment to investigate how ClC-7 affects tooth development and tooth eruption. Firstly, chitosan-Clcn7-siRNA nanoparticles were injected around the first maxillary molar germ of newborn mice and caused the delay of tooth eruption and deformed tooth with root dysplasia. Secondly, E13.5 molar germs infected with Clcn7 shRNA lentivirus were transplanted under the kidney capsule and presented the abnormal changes in dentin structure, periodontal tissue and cementum. All these teeth changes have been reported in the patients with CLCN7 mutation. In vitro studies of ameloblasts, odontoblasts and dental follicle cells (DFCs) were conducted to explore the involved mechanism. We found that Clcn7 deficiency affect the differentiation of these cells, as well as the interaction between DFCs and osteoclasts through RANKL/OPG pathway. We conclude that ClC-7 may affect tooth development by directly targeting tooth cells, and regulate tooth eruption through DFC mediated osteoclast pathway.

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Section: Discussionmentioning

confidence: 99%

ClC-7 Deficiency Impairs Tooth Development and Eruption

Wang

Pan

et al. 2016

Sci Rep

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“…Other actions of GGOH include reversal of zoledronate-induced suppression of inward/outward chloride ion in the acidic environment ( Ohgi et al, 2013 ), and reversal of zoledronate-induced suppression of NFATc1 and carbonyl anhydrase II expression ( Nakagawa et al, 2015 ). In human peripheral mononuclear cells stimulated with RANKL and MCSF, GGOH downregulates tumour necrosis factor (TNF), chemokine ligand (CXCL) 9 and CXCL10, which are upregulated with zoledronic acid treatment ( Zafar et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of Geranylgeraniol in Managing Bisphosphonate-Related Osteonecrosis of the Jaw

Chin

Ekeuku

Trias³

2022

Front. Pharmacol.

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Medication-related osteonecrosis of the jaw (ONJ) is a rare but significant adverse side effect of antiresorptive drugs. Bisphosphonate-related ONJ (BRONJ) is the most prevalent condition due to the extensive use of the drug in cancer and osteoporosis treatment. Nitrogen-containing bisphosphonates suppress osteoclastic resorption by inhibiting farnesyl pyrophosphate synthase in the mevalonate pathway, leading to deficiency of the substrate for GTPase prenylation. The bone remodelling process is uncoupled, subsequently impairing bone healing and causing ONJ. Targeted administration of geranylgeraniol (GGOH) represents a promising approach to mitigate BRONJ because GGOH is a substrate for GTPase prenylation. In the current review, the in vitro effects of GGOH on osteoclasts, osteoblasts and other related cells of the jaw are summarised. We also present and appraise the current in vivo evidence of GGOH in managing BRONJ in animal models. Lastly, several considerations of using GGOH in the clinical management of BRONJ are highlighted. As a conclusion, GGOH is a promising topical agent to manage BRONJ, pending more research on an effective delivery system and validation from a clinical trial.

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“…Бисфосфонаты подавляют резорбтивную активность и усиливают апоптоз остеокластов [23,24]. По химиче-ской структуре бисфосфонаты близки к изопреноидным липидам -фарнезилдифосфату и геранилгеранилдифосфату.…”

Section: применение бисфосфонатов для повышения остеоинтеграции имплаunclassified

The Combined Use of Bisphosphonates and Strontium Ranelate with Osseosubstituting Materials

Хлусов

Венгеровский

Новицкий

2014

ARAMS

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In review the possibility of biomaterials osseointegration improvement with help of bisphosphonates or strontium ranelate is discussed. For this purpose, they are added to hydroxyapatite used for implants coating, or are included as a component of bulk calcium phosphate materials. Strontium is employed as a compound of biodegradable metal alloys, also. Combined use of carrier (implant) with bisphosphonates or strontium ranelate promotes controlling local delivery of pharmaceutical molecules into lesion, enhances the therapy efficiency, and decreases a dose and systemic toxicity of the drugs. Bisphosphonates and strontium ranelate increase the mass, a count and thickness of bone trabeculas, improve the bone biomechanical properties in the place of implants fixation, and diminish the bone fracture risk. Main studies are devoted to pharmacologic mechanisms of implants osseointegration improvement. Bisphosphonates as isoprenoid lipids chemical analogues diminish by concurrent principle the osteoclasts farnesyl pyrophosphate synthase activity and inhibit the prenylation. Unprenylated small GTPases don't fasten onto osteoclasts membrane that weakens cellular resorptive activity and accelerates their apoptosis. Strontium ranelate enhances osteoblasts replicative activity and suppresses their apoptosis, also retards osteoclasts resorptive function and accelerates their apoptosis. Its effects are conditioned by activating Wnt-signaling pathway by means of calcium-sensing receptor and by changing the RANKL/RANK/OPG system.

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A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl− extrusion in osteoclasts

Cited by 8 publications

References 43 publications

ClC-7 Deficiency Impairs Tooth Development and Eruption

ClC-7 Deficiency Impairs Tooth Development and Eruption

The Role of Geranylgeraniol in Managing Bisphosphonate-Related Osteonecrosis of the Jaw

The Combined Use of Bisphosphonates and Strontium Ranelate with Osseosubstituting Materials

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