Zoledronate Inhibits Osteoclast Differentiation via Suppressing Vascular Endothelial Growth Factor Receptor 2 Expression

Nakagawa, Takayuki; Ohta, Kouji; Uetsuki, Ryo; Kato, Hiroki; Naruse, Takako; Murodumi, Hiroshi; Yokoyama, Sho; Sakuma, Miyuki; Ono, Shigehiro; Takechi, Masaaki

doi:10.1007/s10528-020-09961-2

Cited by 8 publications

(7 citation statements)

References 34 publications

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“…The pivotal role of BPs in the impairment of osteoclast differentiation has been demonstrated in MRONJ development (Nakagawa et al., 2020). This study found that 10 –6 M ZOL could suppress osteoclast differentiation but was not cytotoxic to RAW264.7 cells, excluding cytotoxicity as a mechanism of zoledronate in the impairment of osteoclast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of mmu_circ_0001066 attenuates the inhibitory effect of bisphosphonates on osteoclastogenesis

et al. 2021

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Objective Medication‐related osteonecrosis of the jaw (MRONJ) is the main adverse side effect of bisphosphonates (BPs), mainly owing to the inhibitory effect of BPs on osteoclastogenesis. CircRNAs were identified to be an important factor in regulating cellular processes. The aim of this study was to explore the effect of mmu_circ_0001066 on BP‐inhibited osteoclastogenesis. Materials and methods The expression of MRONJ‐related miRNA in RANKL‐induced RAW264.7 cells treated with BP was analyzed using qRT‐PCR analysis. Bioinformatics techniques were applied to screen potential circRNAs. Tartrate‐resistant acid phosphatase (TRAP) staining and bone resorption assays were used to examine the effect of mmu_circ_0001066 on osteoclastogenesis. Bioinformatics analysis, luciferase reporter assays, and Western blotting assays were performed to investigate the underlying mechanism. Results Four MRONJ‐related miRNAs were upregulated in BP‐treated RAW264.7 cells, and the expression of mmu_circ_0001066 was negatively correlated with those of MRONJ‐related miRNAs. Furthermore, the upregulation of mmu_circ_0001066 partially attenuated the inhibitory effect of BP on osteoclastogenesis in RAW264.7 cells. Mechanistically, upregulated miR‐16 suppressed osteoclastogenesis and miR‐16 inhibitor increased osteoclastogenesis. Furthermore, we have identified that miR‐16 is a downstream effector of mmu_circ_0001066. Conclusion Our results suggest that mmu_circ_0001066 played an important role in the BP‐mediated suppression of osteoclastogenesis, which lays a foundation for identifying mmu_circ_0001066 as a potential biomarker for MRONJ.

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Section: Discussionmentioning

confidence: 99%

Upregulation of mmu_circ_0001066 attenuates the inhibitory effect of bisphosphonates on osteoclastogenesis

et al. 2021

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“…A possible explanation for this decreased level of osteoclast formation may be caused by a ZA-induced change in the precursors. Some studies suggested that nitrogen-containing BPs prevent OCPs from differentiating and migrating to osteolysis lesions ( Kimachi et al., 2011 ; Nakagawa et al., 2020 ). We now demonstrated that ZA inhibited osteoclastogenesis by influencing the proportion of certain OCPs subtypes.…”

Section: Discussionmentioning

confidence: 99%

Porphyromonas gingivalis Induces Bisphosphonate-Related Osteonecrosis of the Femur in Mice

Li²,

Tan³

et al. 2022

Front. Cell. Infect. Microbiol.

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One of the most prominent characteristics of bisphosphonate-related osteonecrosis of the jaw(BRONJ) is its site-specificity. Osteonecrosis tends to occur specifically in maxillofacial bones, in spite of a systemic administration of the medicine. Previous studies suggested rich blood supply and fast bone turnover might be reasons for BRONJ. Yet, a sound scientific basis explaining its occurrence is still lacking. The present study aimed to explore the role of Porphyromonas gingivalis (P. gingivalis), an important oral pathogen, on the site-specificity of bisphosphonate-induced osteonecrosis and to elucidate its underlying mechanism. Mice were intraperitoneally injected with zoledronic acid (ZA) or saline for 3 weeks. In the third week, the right mandibular first molars were extracted and circular bone defects with a diameter of 1 mm were created in right femurs. After the operation, drug administration was continued, and P. gingivalis suspension was applied to the oral cavities and femur defects. The mice were killed after four or eight weeks postoperatively. The right mandibles and femurs were harvested for micro-CT and histological analyses. A poor healing of bone defects of both jaws and femurs was noted in mice injected with both ZA and P. gingivalis. Micro-CT analysis showed a decreased bone volume, and histological staining showed an increased number of empty osteocyte lacunae, a decreased collagen regeneration, an increased inflammatory infiltration and a decreased number of osteoclasts. In addition, the left femurs were collected for isolation of osteoclast precursors (OCPs). The osteoclastogenesis potential of OCPs was analyzed in vitro. OCPs extracted from mice of ZA-treated groups were shown to have a lower osteoclast differentiation potential and the expression level of related genes and proteins was declined. In conclusion, we established a mouse model of bisphosphonate-related osteonecrosis of both the jaw and femur. P. gingivalis could inhibit the healing of femur defects under the administration of ZA. These findings suggest that P. gingivalis in the oral cavity might be one of the steering compounds for BRONJ to occur.

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“…The cells were harvested, and their protein was extracted using homogenization in a radioimmunoprecipitation assay buffer (Nacalai Tesque, Kyoto, Japan). Western blotting was performed according to our previous study [17]. In brief, the protein concentration was determined using a Pierce™ BCA Protein Assay kit (Thermo Fisher Scienti c, Waltham, MA, USA).…”

Section: Western Blottingmentioning

confidence: 99%

Inhibition of Angiogenesis and Tumor Progression of Mk-0429, an Integrin Αvβ3 Antagonist, on Oral Squamous Cell Carcinoma

Nakagawa

Ohta²,

Naruse

et al. 2021

Preprint

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PurposeIntegrin αvβ3 is an essential molecule for tumor angiogenesis. This study aimed to investigate the anti-tumor effect of MK-0429, an integrin αvβ3 antagonist, on oral squamous cell carcinoma (OSCC) through its inhibitory effect on angiogenesis.MethodsIn this study, we investigated the effect of MK-0429 on cellular function and angiogenesis in vitro with the use of an immortalized human umbilical vein endothelial cell, HUEhT-1, which is immortalized by the electroporatic transfection of hTERT. The effect of MK-0429 on the integrin αvβ3 signaling pathway was examined by FAK and ERK 1/2 phosphorylation. The anti-angiogenic effect of MK-0429 was evaluated by in vitro tube formation assay. The anti-tumor effect on OSCC was assessed by administrating MK-0429 to mouse oral cancer xenografts.ResultsMK-0429 inhibited cell proliferation, migration, and adhesion of HUEhT-1 in a dose-dependent manner. FAK and ERK phosphorylation were significantly blocked by MK-0429 treatment. Tube formation was suppressed by MK-0429 in dose-dependent manner. Tumor progression was significantly suppressed by MK-0429 administration in mouse oral cancer xenografts. Histological study revealed that MK-0429 decreased tumor vascularization.ConclusionThese results indicated integrin αvβ3 as a therapeutic target for OSCC and suggested that MK-0429 might be clinically applicable as an anti-tumor agent with potent antiangiogenic activity.

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Zoledronate Inhibits Osteoclast Differentiation via Suppressing Vascular Endothelial Growth Factor Receptor 2 Expression

Cited by 8 publications

References 34 publications

Upregulation of mmu_circ_0001066 attenuates the inhibitory effect of bisphosphonates on osteoclastogenesis

Upregulation of mmu_circ_0001066 attenuates the inhibitory effect of bisphosphonates on osteoclastogenesis

Porphyromonas gingivalis Induces Bisphosphonate-Related Osteonecrosis of the Femur in Mice

Inhibition of Angiogenesis and Tumor Progression of Mk-0429, an Integrin Αvβ3 Antagonist, on Oral Squamous Cell Carcinoma

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