Effect of anti-angiogenesis induced by chemotherapeutic monotherapy, chemotherapeutic/bisphosphonate combination therapy and anti-VEGFA mAb therapy on tooth extraction socket healing in mice (original) (raw)
Related papers
Angiogenesis in the Development of Medication-Related Osteonecrosis of the Jaws: An Overview
Dentistry Journal, 2016
Medication-related osteonecrosis of the jaws (MR-ONJ) is one of the most relevant side effects of bisphosphonate therapy; it is clinically defined as a non-healing wound in combination with an avascular and necrotic jaw within ongoing bisphosphonate therapy or after completed bisphosphonate therapy. Different theories concerning the development of MR-ONJ have been reported, while the exact pathophysiology is still unknown. Recent studies have increasingly focused on angiogenesis and revascularization concerning MR-ONJ pathophysiology, which seems to be a relevant factor in the development of MR-ONJ and a possible and promising point of action for MR-ONJ prevention and therapy. Therefore, and with respect to the different aspects and specific forms of angiogenesis, the enclosed review summarizes the possible role of angiogenesis and revascularization in the pathophysiology of MR-ONJ. Special focus is given to the strong negative influence of bisphosphonates on progenitor and mature endothelial cells in vitro as well as on microvessel sprouting in vitro and in vivo, which might result in overall reduced wound healing of oral soft and hard tissues, and therefore in an exposed and avascular jaw from a clinical viewpoint. Further, it will be summarized whether and in what way the aspect of angiogenesis might be used for possible MR-ONJ prevention and therapy.
Journal of Prosthodontic Research
The aim of the present study was to investigate the effects of chemotherapeutic/bisphosphonate combination therapy with tooth extraction on gene expression patterns of fresh extraction wounds during initial stages prior to their diagnosis as bisphosphonate-related osteonecrosis of the jaw (BRONJ)-like lesions in mice. Methods: Female C57BL/6J mice were used. To create a high-prevalence BRONJ mouse model, combination therapy with the chemotherapy drug cyclophosphamide (CY) and zoledronic acid (ZA) was performed (CY/ZA). Both maxillary first molars were extracted 3 weeks after drug therapy. Saline was used as the control (VC). Soft tissues near the fresh extraction wounds were dissected at 72 h postextraction to investigate the gene expression patterns. Maxillae and long bones at 2 and 4 weeks postextraction were also analyzed. Results: CY/ZA significantly increased the relative expression levels of IL-6 and decreased those of IL-10 and IGF-1 when compared with those in VC. Moreover, CY/ZA significantly reduced the relative expression levels of CCR-7, cxcl12, cxcr4, and CD105 when compared with those in VC, whereas the level of F4/80 was significantly increased by CY/ZA. Furthermore, CY/ZA significantly decreased the relative expression levels of VEGFA, VEGFB, and VEGFC at 72 h postextraction compared with those in VC. Conclusions: Considering that the present study lacked adequate in vitro models, CY/ZA markedly changed the gene expression patterns associated with wound healing from the initial stages prior to onset of BRONJ-like lesions, which may help us to understand the pathophysiology of BRONJ in humans.
Osteonecrosis of the Jaw and Angiogenesis inhibitors: A Revival of a Rare but Serous Side Effect
Current Medicinal Chemistry
Osteonecrosis of the jaw (ONJ) is a rare treatment related side effect that was firstly described in 2002 through a case report in metastatic bone cancer patient treated with bisphosphonates (BPs) therapy. ONJ is defined as an eight weeks or longer clinical finding of exposed bone in the oral cavity without response to appropriate therapy. The diagnosis is mainly clinical but often requires a radiological confirmation with an orthopantomography. So it must be made by a dental specialist with sufficient experience on ONJ and requires a detailed anamnestic exploration of comorbidities and treatments history. In particular, ONJ affects a wide number of oncologic patients treated with BPs for bone metastatic cancers and, more recently, with anti-angiogenic drugs. The aim of this this paper is to describe diagnosis and classification of this rare but serious side effect and its pathophysiology. In particular, we provide a detailed description of clinical evidences upon the relationship between anti-angiogenic drugs and ONJ. Considering the evolving of cancer epidemiology with a greater number of cancer surviving patients, this side effect always deserves more attention. We conclude that ONJ must be always carefully investigated and prevented with a multidisciplinary approach involving oncologist, radiation oncologist and skilled dental practitioner when a cancer patient must begin a BP or an anti-angiogenic treatment.
Journal of Oral and Maxillofacial Surgery, 2019
This study aimed to explore the effect of the chemotherapeutic agent bevacizumab on the extraction socket healing process in New Zealand rabbits. Materials and Methods: The animals received intraperitoneal bevacizumab treatment for 6 consecutive weeks (3 mg/kg per week). The right mandibular first premolar was extracted in the second week of the experiment, and the jaw bone containing the socket tissues was harvested at the end of the treatment period. The healing of the removed socket was analyzed histologically and radiographically using a micro-computed tomography scan. Results: Quantitative morphometric and histologic assessments of the healing process of the extraction sockets in rabbits showed a marked (P #.05) decrease in the bone volumetric mass after angiogenesis suppression by bevacizumab therapy (n = 5) compared with the control group (n = 5). Conclusions: The results of this study indicate the physiological significance of angiogenesis in extraction socket healing. Moreover, this study highlights the risks and precautions that should be considered in clinical practice in patients undergoing targeted chemotherapy.
Bone, 2013
Melphalan Wound healing Osteonecrosis of the jaw Lymphangiogenesis Osteonecrosis of the jaw (ONJ) is a serious adverse event that occurs predominantly in patients on both antiresorptive and antineoplastic therapies. However, how these combination therapies are connected to the high frequency of ONJ in this particular patient population is unclear. This study's aim was to determine a mechanism of ONJ associated with the combination therapy of antiresorptives and chemotherapeutics. Mice received zoledronic acid (ZA) in conjunction with melphalan or dexamethasone. The maxillary first molars were extracted 3 weeks after the initiation of treatment and wound healing assessed at 4 weeks post-extractions using microcomputed tomography and immunohistochemistry. Mice receiving the combination treatment of ZA and melphalan developed ONJ-like lesions, while ONJ-like lesions were not found in mice on ZA or melphalan monotherapy, or the combination treatment of ZA and dexamethasone. ONJ lesions were characterized by a lack of epithelium, exposed necrotic bone, severe inflammatory cell infiltration, and minimal bone formation. Fluorescent immunohistochemistry showed that lymphatic vessel formation was significantly suppressed in ONJ-like lesions with a concomitant decrease in F4/80 + macrophages expressing vascular endothelial growth factor C (VEGFC). Interestingly, significantly suppressed lymphatics were also found in the draining lymph nodes of mice on the combination treatment of ZA and melphalan. Thus, suppressed lymphangiogenesis was strongly associated with the development of ONJ-like lesions in the current study. Since lymphangiogenesis is critical in the resolution of inflammation during wound healing, inflammation control may serve as a potential strategy to prevent ONJ.
The Journal of the American Dental Association, 2012
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) worsens oral health-related quality of life. Most BRONJ occurs in multiple myeloma or metastatic breast cancer patients treated with bisphosphonate/chemotherapeutic combination therapies. Cyclophosphamide (CY), an alkylating chemotherapeutic drug, is used to treat multiple myeloma, although its use has been recently reduced. The aim of this study was to clarify the effects of CY dose on tooth extraction socket healing when CY is used with or without bisphosphonate in mice. Low-dose CY (50 mg/kg; CY-L), moderate-dose CY (100 mg/kg; CY-M), high-dose CY (150 mg/kg; CY-H), and bisphosphonate [Zometa (ZA): 0.05 mg/kg] were administered for 7 weeks. Each dose of CY and ZA in combination was also administered for 7 weeks. Both maxillary first molars were extracted at 3 weeks after the initiation of drug administration. Euthanasia was performed at 4 weeks post-extraction. Gross wound healing, microcomputed tomography analysis, histomorphometry, and immunohistochemistry were used to quantitatively evaluate osseous and soft tissue wound healing of tooth extraction sockets. ZA monotherapy induced no BRONJ-like lesions in mice. CY monotherapy rarely induced open wounds, though delayed osseous wound healing occurred in a CY dose-dependent manner. In contrast, CY/ZA combination therapy prevalently induced BRONJ-like lesions with compromised osseous and soft tissue healing in a CY dose-dependent manner. Interestingly, anti-angiogenesis was noted regardless of CY dose and ZA administration, even though only CY-M/ ZA and CY-H/ZA combination therapies induced BRONJ-like lesions. Our findings suggest that high-dose CY may be associated with the development of BRONJ following tooth extraction only when CY is used together with ZA. In addition to anti-angiogenesis, other factors may contribute to the pathoetiology of BRONJ.
Bone, 2020
There is limited information about denosumab-related osteonecrosis of the jaw (DRONJ), unlike bisphosphonate-related ONJ (BRONJ). The mode of action is clearly different between denosumab and bisphosphonates. DRONJ occurs mainly following tooth extraction in cancer patients treated with the combination of denosumab and other drugs including chemotherapy. However, DRONJ animal models similar to these clinical situations have not been developed. The aims of this study were to 1) create a new model of high-prevalence chemotherapy/anti-RANKL antibody-related ONJ-like lesions to mimic patients receiving a denosumab/chemotherapy combination; and 2) compare the histopathological and immunopathological findings in the early stages of BRONJ-like and anti-RANKL antibody-related ONJ-like lesions. Cyclophosphamide (CY) and antimouse RANKL monoclonal antibody (mAb) or zoledronate combination therapy (CY/mAb and CY/ZA, respectively) was performed to create ONJ-like lesions in female C57BL/6J mice. Both maxillary first molars were extracted at 3 weeks after drug administration. The animals were euthanized at either 2 or 4 weeks after tooth extraction. Increased necrotic bone and empty lacunae with decreased living bone and osteocyte numbers were common histopathological findings in CY/mAb-and CY/ZA-induced impaired wound healing at 4 weeks after tooth extraction, and they were diagnosed as ONJ-like lesions based on validation of BRONJ and DRONJ in humans. In areas of impaired healing at 2 weeks post-extraction, decreases in angiogenesis and F4/80 + LYVE-1 − macrophages were noted as common immunopathological findings, although anti-angiogenesis was worse with CY/mAb than with CY/ZA. Interestingly, CY/mAb did not reduce F4/80 + LYVE-1 + cells and normal lymphangiogenesis remained, whereas CY/ZA profoundly suppressed the larger size of F4/80 + LYVE-1 + cells, similar to vessels with a concomitant decrease in lymphangiogenesis. Therefore, the distribution of the larger size of F4/80 + LYVE-1 + cells differed in the early stages between different antiresorptive-induced ONJ-like lesions in conjunction with lymphangiogenesis, although the histopathological findings were similar. These findings suggest that the pathogenesis of BRONJ and DRONJ may differ due to the distributions of F4/80 + LYVE-1 + tubelike-structured cells.
Antiresorptive Agents and Anti-Angiogenesis Drugs in the Development of Osteonecrosis of the Jaw
The Tohoku Journal of Experimental Medicine
Medication-related osteonecrosis of the jaw (MRONJ) is a condition of exposed bone in the maxillofacial region, which occurs among subjects treated with antiresorptive agents or anti-angiogenesis drugs, despite the lack of a history of head or neck radiation treatment. Although there are still many points to be clarified about the mechanism of MRONJ, it is possible to hypothesize a common pathogenetic mechanism for two different classes of drugs: antiresorptive and anti-angiogenetic drugs. These drugs can inhibit angiogenesis by interfering with endothelial cell proliferation and survival, leading to loss of blood vessels and avascular necrosis. This hypothesis could be of immediate translational interest. Targeting the anti-angiogenetic effect of the antiresorptive agents could provide a new possibility for the prevention of treatment of MRONJ.
The Journal of biological chemistry, 2016
Injury to the barrier tissue initiates a rapid distribution of myeloid immune cells from bone marrow, which guide sound wound healing. Bisphosphonates, a widely used anti-bone resorptive drug with minimal systemic side effects, have been linked to an abnormal wound healing in the oral barrier tissue leading to, in some cases, osteonecrosis of the jaw (ONJ). Here we report that the development of ONJ may involve abnormal phenotypic plasticity of Ly6G+/Gr1+ myeloid cells in the oral barrier tissue undergoing tooth extraction wound healing. A bolus intravenous zoledronate (ZOL) injection to female C57Bl/6 mice followed by maxillary first molar extraction resulted in the development of ONJ-like lesion during the second week of wound healing. The multiplex assay of dissociated oral barrier cells exhibited the secretion of cytokines and chemokines, which was significantly modulated in ZOL mice. Tooth extraction-induced distribution of Ly6G+/Gr1+ cells in the oral barrier tissue increased ...
Angiogenesis and the prevention of alveolar osteitis: a review study
Journal of the Korean Association of Oral and Maxillofacial Surgeons, 2018
Angiogenesis is one of the essential processes that occur during wound healing. It is responsible for providing immunity as well as the regenerative cells, nutrition, and oxygen needed for the healing of the alveolar socket following tooth extraction. The inappropriate removal of formed blood clots causes the undesirable phenomenon of alveolar osteitis (AO) or dry socket. In this review, we aimed to investigate whether enhanced angiogenesis contributes to a more effective prevention of AO. The potential pro-or anti-angiogenic activity of different materials used for the treatment of AO were evaluated. An electronic search was performed in the PubMed, MEDLINE, and EMBASE databases via OVID from January 2000 to September 2016 using the keywords mentioned in the PubMed and MeSH (Medical Subject Headings) terms regarding the role of angiogenesis in the prevention of AO. Our initial search identified 408 articles using the keywords indicated above, with 38 of them meeting the inclusion criteria set for this review. Due to the undeniable role of angiogenesis in the socket healing process, it is beneficial if strategies for preventing AO are directed toward more proangiogenic materials and modalities.