The role of MAPK-activated protein kinase-2 and -3 in bone homeostasis and inflammatory bone destruction

炎症是破骨细胞介导的骨质流失的强烈触发因素。类风湿性关节炎（RA）是一种骨破坏疾病的原型。促炎介质对炎性骨溶解的发病机制至关重要。例如，TNF是体外和体内破骨细胞生成的强烈触发器。细胞内信号转导通路在桥接炎症与骨质流失的过程中起关键作用是丝裂原活化蛋白激酶（MAPK），其中之一是p38MAPK。主要下游靶点是mapk活化蛋白激酶-2 （MK2）和-3 （MK3）。我们的初步数据为MK2在破骨细胞生成和炎症中的重要作用提供了证据。在本项目中，我们将重点关注MK2和MK3作为正常骨稳态和炎症性骨溶解的介质的作用。我们将结合体外方法，使用功能性破骨细胞和成骨细胞测定和分子生物学技术来鉴定MK2和MK3的靶基因。我们将在体内使用MK2和MK3缺陷小鼠来评估MK2和MK3是否在正常骨稳态中发挥作用。此外，我们将在这些小鼠中建立不同的骨质流失动物模型：绝经后骨质流失（卵巢切除术），局部炎症性骨质流失（LPS模型）和炎症性骨质减少（TNF转基因小鼠模型）。这些实验将明确MK2和MK3在骨质流失发病机制中的作用，并有助于确定治疗这种有害疾病的新靶点。

Inflammation is a strong trigger for osteoclast-mediated bone loss. Rheumatoid arthritis (RA) is the prototype of a bone destructive disease. Pro-inflammatory mediators are essential for the pathogenesis of inflammatory osteolysis. TNF for instance is a strong trigger of osteoclastogenesis in vitro and in vivo. Intracellular signal transduction pathways of key importance in bridging inflammation with bone loss are the mitogen-activated protein kinases (MAPK), one of them is p38MAPK. The main downstream targets are MAPK-activated protein kinase-2 (MK2) and -3 (MK3). Our preliminary data provide evidence for an important role of MK2 in osteoclastogenesis and inflammation. In this project, we will focus on the role of MK2 and MK3 as mediators of normal bone homeostasis and inflammatory osteolysis. We will combine in vitro approaches using functional osteoclast and osteoblast assays and molecular biology techniques to identify target genes of MK2 and MK3. We will assess whether MK2 and MK3 play a role in normal bone homeostasis using MK2 and MK3-deficient mice in vivo. Further, we will perform different animal models of bone loss in these mice: postmenopausal bone loss (ovariectomy), local inflammatory bone loss (LPS model) and inflammatory osteopenia (TNF transgenic mouse model). These experiments will define the role of MK2 and MK3 in the pathogenesis of bone loss and help to identify new targets for the treatment of this deleterious condition.