Mechanisms of inflammatory bone remodeling

 描述（由申请人提供）：成人骨骼的完整性经历持续和动态重塑以维持骨稳态，这是通过严格控制破骨细胞介导的骨吸收和成骨细胞介导的骨形成之间的偶联来实现的。然而，这种骨重建过程的平衡在病理条件下被破坏。慢性炎症是最明显和最常见的病理环境之一，其通常导致以过度骨丢失但骨形成有限为特征的失调的骨重建，例如发生在类风湿性关节炎（RA）、牙周炎和牙周炎-假体松动中。这些疾病中骨重建的紊乱对目前的抗吸收治疗是难治的，并导致持续的肌肉骨骼组织损伤和加速发病。在病理条件下影响骨重建失调的机制在很大程度上是未知的，这是成功治疗与骨丢失相关的许多疾病的障碍。 我们的长期目标是确定和了解炎症环境中调节骨重建的机制，并利用这些知识开发新的治疗方法来治疗与炎症性骨质溶解相关的疾病。我们对TNF-α介导的骨重建特别感兴趣， 因为TNF-α是驱动炎性骨吸收的关键致病因子。我们最近鉴定了Def 6，其在生理条件和TNF-α介导的炎症环境中作为骨重建的新型调节剂发挥作用。Def 6抑制破骨细胞分化，同时增强成骨细胞分化对TNF-α刺激的反应。重要的是，Def 6表达水平被TNF-α下调，并且与RA患者中的TNF-α水平负相关，表明Def 6在RA中失调的骨重建的发病机制中具有潜在的重要作用。 在本申请中，我们将应用遗传学方法，并使用体外细胞培养系统和关节炎动物模型来研究：1）Def 6调节骨重建因子的机制，重点是Def 6对DKK 1表达和DKK 1-Wnt介导的重建轴的表观遗传调节; 2）Def 6调节破骨细胞和成骨细胞分化的机制;和3）在炎性关节炎动物模型中使用Def 6功能的丧失和获得，Def 6在炎性关节炎骨吸收中的功能重要性。将进行Def 6的结构-功能分析，以鉴定对Def 6在骨重建中的功能重要的结构域和/或磷酸化位点。我们预计，我们的研究将深入了解抑制炎性骨质溶解的机制，并将有助于开发新的治疗方法来抑制炎症环境中的骨吸收。

 DESCRIPTION (provided by applicant): The integrity of the adult skeleton undergoes constant and dynamic remodeling to maintain bone homeostasis, which is achieved by the tight control of coupling between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. However, the balance of this bone remodeling process is disrupted in pathological conditions. Chronic inflammation is one of the most evident and common pathological settings that often lead to deregulated bone remodeling characterized by excessive bone loss but limited bone formation, such as occurs in rheumatoid arthritis (RA), periodontitis and peri- prosthetic loosening. The disturbances in bone remodeling in these diseases are refractory to current antiresorptive treatments and lead to continuous musculoskeletal tissue damage and accelerating pathogenesis. The mechanisms that impact the deregulated bone remodeling in pathological conditions are largely unknown, which is a barrier to successfully treating the numerous diseases associated with bone loss. Our long term goals are to identify and understand the mechanisms that regulate bone remodeling in inflammatory settings, and to utilize this knowledge in development of new therapeutic approaches to diseases associated with inflammatory osteolysis. We are particularly interested in TNF- mediated bone remodeling since TNF- is a key pathogenic factor driving inflammatory bone resorption. We have recently identified Def6 that functions as a novel regulator of bone remodeling in both physiological conditions and TNF--mediated inflammatory settings. Def6 suppresses osteoclast differentiation while enhancing osteoblast differentiation in response to TNF- stimulation. Importantly, Def6 expression levels are downregulated by TNF- and inversely correlate with TNF- levels in RA patients, indicating a potentially important role of Def6 in the pathogenesis of deregulated bone remodeling in RA. In this application, we will apply genetic approaches and use both in vitro cell culture systems and arthritis animal models to investigate: 1) the mechanisms by which Def6 regulates bone remodeling factors, with a focus on the epigenetic regulation of DKK1 expression and the DKK1-Wnt mediated remodeling axis by Def6; 2) the mechanisms by which Def6 regulates both osteoclast and osteoblast differentiation; and 3) the functional importance of Def6 in inflammatory arthritic bone resorption using both loss and gain of function of Def6 in inflammatory arthritis animal models. A structure-function analysis of Def6 will be performed to identify the domain(s) and/or phosphorylation site(s) that are important for Def6 function in bone remodeling. We anticipate that our studies will yield insight into mechanisms that restrain inflammatory osteolysis, and will be useful in developing new therapeutic approaches to suppressing bone resorption in inflammatory settings.