Role of pro-inflammatory cytokines in drug induced osteonecrosis of the jaw

 说明(申请人提供)：双膦(BP)是一类抗吸收药物，长期以来一直被用于治疗骨质疏松症和癌症患者的骨转移等骨病。像BPS这样的抗吸收药物的副作用是，长期服用BRONJ的风险更高，BRONJ的临床定义是裸露的坏死骨和未封闭的覆盖口腔粘膜至少8周。BRONJ的病理生理学一直备受争议，很可能是由于BPS的多效性作用。最近，我们已经证明，由于BP给药而导致破骨细胞功能障碍的小鼠，在拔牙后约30%的时间会出现ONJ样病变。虽然该领域的许多研究小组正在努力了解破骨细胞功能障碍是如何导致BRONJ的，我们已经揭示了破骨细胞功能减弱是必要的，但还不足以引发BRONJ。为了了解BRONJ的发育还涉及哪些其他因素，我们通过对活检组织进行微阵列分析，确定了潜在的相关基因，特别是IL-36。我们已经在体外和体内验证了这一测试的结果，表明IL的诱导 36 BP抑制细胞外基质蛋白(即胶原前体)，这是伤口愈合过程中上皮化所必需的，这种抑制可能是BRONJ发生的一个病因。我们研究的长期目标是了解BRONJ的分子机制，并利用这种疾病模型更好地了解骨粘膜伤口的愈合。在目前的研究中，我提出了一个假设，即IL-36是参与骨关节发育的关键细胞因子，IL-36信号通路通过核因子ĸB及其下游介质抑制骨形成和伤口愈合。根据我们的初步数据，我的目标是：1)确定IL-36抑制胶原表达的机制；2)研究IL-36信号在体内的直接作用；3)研究IL-36 表达是BRONJ诱导的危险因素。BRONJ的问题不能通过减少或取消治疗来解决，因为潜在的情况(如骨质疏松症、转移性癌症)更为严重，必须加以解决。因此，确定BRONJ发生的原因，如何预测其发生，并建立治疗方法对于那些 都会经历这种情况。当前项目的成功完成将解决所有这些问题，并为了解这种痛苦疾病的病因做出重大贡献。这一奖项将为学员作为伤口愈合和骨生物学的独立研究员的学术生涯做好准备。

 DESCRIPTION (provided by applicant): Bisphosphonates (BP), a class of anti-resorptive drugs, have a long history of being prescribed to treat bone disorders like osteoporosis and bone metastases in cancer patients. A side effect of anti-resorptive drugs like BPs is that long-term users are at a higher risk of developing BRONJ, which is clinically defined as exposed necrotic bone and unclosed overlaying oral mucosa for at least 8 weeks. The pathophysiology of BRONJ is highly debated most likely due to the pleiotropic effects of BPs. Recently, we have demonstrated that mice with dysfunctional osteoclasts due to BP administration manifest ONJ-like lesions about 30% of the time following dental extraction. While many groups in the field are working to understand how osteoclast dysfunction leads to BRONJ, we have revealed that diminished osteoclast function is required, but not sufficient to induce BRONJ. In order to understand what other factors are involved in BRONJ development, we have identified potential genes involved, specifically IL-36, by performing microarray analysis on biopsied tissues. We have validated the results of this assay both in vitro and in vivo, suggesting that induction of IL 36 by BP leads to suppression of extracellular matrix proteins (i.e. collagen precursors), which are required for re-epithelialization during wound healing, and this suppression may be an etiological factor in BRONJ development. The long- term goal of our research is to understand the molecular mechanisms that give rise to BRONJ and use this disease model to better understand osteomucosal wound healing. In the current study, I propose a hypothesis that IL-36 is a critical cytokine involved in ONJ development and that the IL-36 signaling pathway inhibits bone formation and wound healing via NFĸB and its downstream mediators. Based on our preliminary data, I aim to: 1) Determine the mechanism by which IL-36 inhibits collagen expression; 2) Investigate the direct effects of IL- 36 signaling in vivo; and 3) Investigate IL-36 expression as a risk factor for BRONJ induction. The issue of BRONJ cannot be resolved by reducing or eliminating treatment as the underlying conditions (e.g. osteoporosis, metastatic cancer) are more severe and must be addressed. Thus, determining why BRONJ occurs, how to predict its occurrence, and establishing therapeutic treatments is critical for the patients who will experience this condition. Successful completion of the current project will address all of these issues and make significant contributions to understanding the etiopathogenesis of this painful malady. This award will prepare the trainee for an academic career as an independent researcher in wound healing and bone biology.