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

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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.