Restriction of nidogen containing bisphosphonates- related osteonecrosis (BRONJ) to the jaw bone - Immunohistochemistry and molecular biology assessment of the animal BRONJ- model in the the Wistar- rat

含有双磷酸盐相关性骨坏死 (BRONJ) 的巢蛋白对颌骨的限制 - Wistar 大鼠动物 BRONJ 模型的免疫组织化学和分子生物学评估

• 批准号: 232352343
• 负责人: Privatdozent Dr. Falk Wehrhan, Ph.D.
• 金额: --
• 依托单位: Pathologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/232352343?language=en
• 关键词: Restriction; nidogen; containing; bisphosphonates; related

No accepted etiology of the Bisphosphonate related osteonecrosis of the jaw (BRONJ) is available at present. BRONJ is characterized by intraoral exposed bone, osteopetrotic changes of the bone, impaired intraoral hard- and soft tissue healing and inflammation. Aminobisphosphonate (BP)- related toxicity to tissues or BP-related local inflammation as underlying mechanisms have been proposed in the past. This is not likely, however, since the identical clinical picture of BRONJ is presented following therapy with Denosumab, a monoclonal anti-Rank(L) antibody. The unique biologic feature of jaw bone is represented by its developmental biology related origin from the cranial neural crest cells (CNC), which implies CNC-related signal transduction of osseous remodelling within jaw bones. Msx-1 is exclusively expressed in CNC-derived osseous structures and pivotal to CNC-derived tissue remodeling. Own results showed suppression of Msx-1 and Rank(L) in BP-altered jaw bone at protein- and mRNA-level. Furthermore BP were shown to induce polarization of macrophages towards the inflammation-related M1 type. Rank(L) is essentially involved in signal transduction of jaw bone osseous remodelling and macrophage differentiation. Thus, impaired Msx-1/ Rank(L)-signalling could explain BP- and Denosumab specific osteonecrosis of the jaw.This experimental project (model wistar rat) shall clarify if BP treatment leads to differential impairment of bone remodelling and macrophage differentiation in jaw bone compared with extracranial mesenchymal determined tibia bone. The aim of this study is to quantitatively compare the expression patterns of Msx-1, Msx-2, Bmp-2/4, Dlx-5, Runx-2, Rank(L) during healing of an extraction socket and a tibia fracture following application of zoledronic acid. Furthermore, it shall be clarified if BP preferentially interact with Connexin-43 expressing osseous neural crest derived structures as described in literature. The results of the project will provide information describing the formal pathology of BRONJ. Moreover, the data of the project will elucidate the site specific signal transduction of osseous remodelling in jaw bones and the possible specific osteoimmunologic microenvironment. The results of the study might help to enable the evidence based therapeutic use of BP and Denosumab treating jaw bone specific osteoproliferative and inflammatory diseases like cherubism, ossifying fibroma and primary chronic osteomyelitis.

目前尚无双膦酸盐相关颌骨骨坏死（BRONJ）的公认病因。BRONJ的特征在于口内暴露的骨、骨的骨硬化性变化、口内硬组织和软组织愈合受损以及炎症。过去已经提出氨基二膦酸盐（BP）相关的组织毒性或BP相关的局部炎症作为潜在机制。然而，这不太可能，因为在使用Denosumab（一种单克隆抗Rank（L）抗体）治疗后，BRONJ的临床表现相同。颌骨独特的生物学特征表现为其发育生物学相关的起源于颅神经嵴细胞（CNC），这暗示颌骨内存在与CNC相关的骨改建信号传导。Msx-1仅在CNC衍生的骨结构中表达，并对CNC衍生的组织重塑起关键作用。自己的研究结果表明，在蛋白质和mRNA水平上，BP改变的颌骨中Msx-1和Rank（L）受到抑制。此外，BP显示出诱导巨噬细胞向炎症相关的M1型极化。Rank（L）主要参与颌骨骨改建和巨噬细胞分化的信号转导。因此，受损的Msx-1/ Rank（L）-信号传导可以解释BP-和Denosumab特异性颌骨骨坏死。本实验项目（Wistar大鼠模型）将阐明，与颅外间充质决定的胫骨相比，BP治疗是否导致颌骨骨重塑和巨噬细胞分化的差异性损伤。本研究的目的是定量比较应用唑来膦酸后拔牙窝和胫骨骨折愈合过程中Msx-1、Msx-2、Bmp-2/4、Dlx-5、Runx-2、Rank（L）的表达模式。此外，应澄清BP是否优先与文献中描述的表达连接蛋白-43的骨神经嵴衍生结构相互作用。该项目的结果将提供描述BRONJ正式病理学的信息。此外，本项目的数据将阐明颌骨骨重建的位点特异性信号转导和可能的特异性骨免疫微环境。研究结果可能有助于BP和Denosumab治疗颌骨特异性骨增殖性和炎症性疾病（如巨颌症、骨化性纤维瘤和原发性慢性骨髓炎）的循证治疗用途。