Mechanisms of inflammatory bone remodeling

 描述(申请人提供)：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，成人骨骼的完整性经历了持续和动态的重塑，以维持骨稳态。然而，在病理条件下，这种骨重建过程的平衡被打破。慢性炎症是最明显和最常见的病理环境之一，经常导致以过度骨丢失但骨形成有限为特征的失调性骨重建，如类风湿性关节炎(RA)、牙周炎和假体周围松动。这些疾病中的骨重建障碍对目前的抗吸收治疗是困难的，并导致持续的肌肉骨骼组织损伤和加速发病。在病理条件下影响失调性骨重建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众多疾病的障碍。我们的长期目标是识别和了解炎症环境中骨重塑的调节机制，并利用这些知识开发与炎性骨溶解相关的疾病的新治疗方法。我们对肿瘤坏死因子-介导的骨重建特别感兴趣。 因为肿瘤坏死因子-是导致炎症性骨吸收的关键致病因子。我们最近发现，在生理条件和肿瘤坏死因子-介导的炎症环境中，Def6都作为一种新的骨重建调节因子发挥作用。在肿瘤坏死因子-刺激下，Def6抑制破骨细胞分化，而促进成骨细胞分化。重要的是，在RA患者中，Def6的表达水平受肿瘤坏死因子-的下调，并且与肿瘤坏死因子-的水平呈负相关，提示Def6在RA失调性骨重建的发病机制中具有潜在的重要作用。在这项应用中，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)Def6调节骨重建因子的机制，重点是Def6对Dkk1表达和Dkk1-Wnt介导的重建轴的表观遗传调控；2)Def6调节破骨细胞和成骨细胞分化的机制；以及3)Def6在炎性关节炎动物模型中通过失去和获得Def6的功能而在炎症性关节炎骨吸收中的功能重要性。将通过对Def6的结构-功能分析来确定在骨重建中对Def6功能起重要作用的结构域(S)和/或磷酸化位点(S)。我们预计，我们的研究将深入了解抑制炎性骨溶解的机制，并将有助于开发新的治疗方法，以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.