Impaired Bone Resorption and Woven Bone Formation Are Associated with Development of Osteonecrosis of the Jaw-Like Lesions by Bisphosphonate and Anti–Receptor Activator of NF-κB Ligand Antibody in Mice

Williams, D.; Lee, Cindy; Kim, Terresa; Yagita, Hideo; Wu, Hongkun; Park, Sil; Yang, Paul; Liu, Honghu; Shi, Songtao; Shin, Kihyuk; Kang, Mo K.; Park, No-Hee; Kim, Reuben H.

doi:10.1016/j.ajpath.2014.07.010

Cited by 76 publications

(88 citation statements)

References 33 publications

(34 reference statements)

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“…In addition, a decrease in osteoblasts number was observed in the long bones after 3 weeks of systemic treatment with increasing doses of ZOL (Pozzi et al 2009). Moreover, the absence of woven bone in the alveolar socket after tooth extraction in mice treated with bisphosphonate and denosumab, two agents associated with osteonecrotic-lesions, has recently been demonstrated (Williams et al 2014). In this study, seric levels of bone-specific alkaline phosphatase, a biomarker of osteoblastic cell activity, was also decreased (Williams et al 2014).…”

Section: Discussionmentioning

confidence: 49%

“…Moreover, the absence of woven bone in the alveolar socket after tooth extraction in mice treated with bisphosphonate and denosumab, two agents associated with osteonecroticlesions, has recently been demonstrated (Williams et al 2014). In this study, seric levels of bone-specific alkaline phosphatase, a biomarker of osteoblastic cell activity, was also decreased (Williams et al 2014). Similarly, a cytotoxic effect characterized by the inhibition of viability, bone matrix secretion and mineralization was observed in osteoblasts after prolonged exposure to ZOL under in vitro conditions (Pozzi et al 2009).…”

Section: Discussionmentioning

confidence: 99%

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Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

Córdova

Guilbaud

Amiaud

et al. 2016

Journal of Cranio-Maxillofacial Surgery

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Objectives: The effect of amino-bisphosphonates on osteoblastic lineage and its potential contribution to the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BONJ) remain controversial. We assessed the effects of zoledronic acid (ZOL) on bone and vascular cells of the alveolar socket using a mouse model of BONJ. Material and methods: Thirty-two mice were treated twice a week with either 100 mu g/kg of ZOL or saline for 12 weeks. The first left maxillary molar was extracted at the third week. Alveolar sockets were assessed at both 3 weeks (intermediate) and 9 weeks (long-term) after molar extraction by semi quantitative histomorphometry for empty lacunae, preosteoblasts (Osterix), osteoclasts (TRAP), and pericyte-like cells (CD146). Also, the bone microarchitecture was assessed by micro-CT. Results: Osteonecrotic-like lesions were observed in 21% of mice. Moreover, a decreased number of preosteoblasts contrasted with the increased number of osteoclasts at both time points. In addition, osteoclasts display multinucleation and detachment from the endosteal surface. Furthermore, the number of pericyte-like cells increased at the intermediate time point. The alveolar bone mass increased exclusively with long-term ZOL treatment. Conclusion: The severe imbalance between bone-forming cells and bone-resorbing cells shown in this study could contribute to the pathogenesis of BONJ

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

Córdova

Guilbaud

Amiaud

et al. 2016

Journal of Cranio-Maxillofacial Surgery

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“…Previously, we have established the mouse model for BRONJ and showed that tooth extraction alone induces ONJ (10). Here, we hypothesize that pre-existing inflammatory conditions exacerbate BRONJ development following tooth extraction.…”

Section: Introductionmentioning

confidence: 99%

Preexisting Periapical Inflammatory Condition Exacerbates Tooth Extraction–induced Bisphosphonate-related Osteonecrosis of the Jaw Lesions in Mice

Song

Alshaikh

Kim

et al. 2016

Journal of Endodontics

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Introduction Surgical interventions such as tooth extraction increase a chance of developing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BPs) for treatment of bone-related diseases. Tooth extraction is often performed to eliminate pre-existing pathological inflammatory conditions that make the tooth unsalvageable; however, the role of such conditions on bisphosphonate-related ONJ (BRONJ) development following tooth extraction is not clearly defined. Here, we examined the effects of periapical periodontitis on tooth extraction-induced BRONJ development in mice. Methods Periapical periodontitis was induced by exposing the pulp of the maxillary first molar for 3 weeks in C57/BL6 mice that were intravenously administered with BP. The same tooth was extracted, and after 3 additional weeks, the mice were harvested for histological, histomorphometric, and histochemical staining analyses. Results Pulp exposure induced periapical radiolucency as demonstrated by increased inflammatory cells, TRAP+ osteoclasts, and bone resorption. When BP was administered, pulp exposure did not induce apical bone resorption despite the presence of inflammatory cells and TRAP+ osteoclasts. While tooth extraction alone induced BRONJ lesions, pulp exposure further increased tooth extraction-induced BRONJ development as demonstrated by the presence of more bone necrosis. Conclusion Our study demonstrates that pre-existing pathological inflammatory condition such as periapical periodontitis is a predisposing factor that may exacerbate BRONJ development following tooth extraction. Our study further provides a clinical implication whereby periapical periodontitis should be controlled before performing tooth extraction in BP-users in order to reduce the risk of developing BRONJ.

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“…For example, Rank (L) has been reported to be differentially induced in vitro, depending on the BP concentration [39]. Despite this in vitro finding, suppression of Rank (L) is known to be an important antiresorptive mechanism of BP in the clinical in vivo use [51].…”

mentioning

confidence: 98%

BRONJ-related jaw bone is associated with increased Dlx-5 and suppressed osteopontin—implication in the site-specific alteration of angiogenesis and bone turnover by bisphosphonates

et al. 2014

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Objectives Site-specific suppression of bone remodelling has been implicated in bisphosphonate-(BP)-related osteonecrosis of the jaws (BRONJ). Due to the origin of jaw bone from cranial neural crest, osseous differentiation is regulated specifically by the antagonizing BMP-2-downstream-transcription factors Msx-1 and Dlx-5. Osteopontin has been implicated in bone remodelling and angiogenesis. The osteoblast and osteoclast progenitor proliferation mediating Msx-1 has been demonstrated to be suppressed in BRONJ. In vitro BPs were shown to increase Dlx-5 and to suppress osteopontin expression. This study targeted Dlx-5 and osteopontin in BRONJ-related and BP-exposed jaw bone compared with healthy jaw bone samples at protein-and messenger RNA (mRNA) level, since increased Dlx-5 and suppressed osteopontin might account for impaired bone turnover in BRONJ. Materials and methods Fifteen BRONJ-exposed, 15 BPexposed and 20 healthy jaw bone samples were processed for real-time reverse transcription polymerase chain reaction (RT-PCR) and for immunohistochemistry. Targeting Dlx-5, osteopontin and glyceraldehyde 3-phosphate dehydrogenase mRNA was extracted, quantified by the LabChip-method, followed by quantitative RT-PCR. For immunohistochemistry, an autostaining-based alkaline phosphatase antialkaline phosphatase (APAPP) staining kit was used. Semiquantitative assessment was performed measuring the ratio of stained cells/ total number of cells (labelling index, Bonferroni adjustment). Results The labelling index was significant decreased for osteopontin (p<0.017) and significantly increased for Dlx-5 (p<0.021) in BRONJ samples. In BRONJ specimens, a significant fivefold decrease in gene expression for osteopontin (p<0.015) and a significant eightfold increase in Dlx-5 expression (p<0.012) were found. Conclusions BRONJ-related suppression of bone turnover is consistent with increased Dlx-5 expression and with suppression of osteopontin. The BP-related impaired BMP-2-Msx-1-Dlx-5 axis might explain the jaw bone specific alteration by BP. Clinical relevance The findings of this study help to explain the restriction of RONJ to craniofacial bones. BRONJ might serve as a model of disease elucidating the specific signal transduction of neural crest cell-derived bone structures in health and disease.

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Impaired Bone Resorption and Woven Bone Formation Are Associated with Development of Osteonecrosis of the Jaw-Like Lesions by Bisphosphonate and Anti–Receptor Activator of NF-κB Ligand Antibody in Mice

Cited by 76 publications

References 33 publications

Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw

Preexisting Periapical Inflammatory Condition Exacerbates Tooth Extraction–induced Bisphosphonate-related Osteonecrosis of the Jaw Lesions in Mice

BRONJ-related jaw bone is associated with increased Dlx-5 and suppressed osteopontin—implication in the site-specific alteration of angiogenesis and bone turnover by bisphosphonates

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