The role of WAVE Complex in osteoclast-mediated bone destruction in experimental arthritis

• Applicants: Berno Dankbar, Ph.D.; Professorin Dr. Theresia Stradal
• Subject Area: Rheumatology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456073691

Migration, adhesion as well as endo- and exocytosis all critically depend on dynamic reorganization of the actin cytoskeleton, potentially involving actin nucleators like Arp2/3-complex and its activators such as WAVE-complex. In order to investigate the role of WAVE-complex in the hematopoietic system, we have generated mice in which the gene encoding the only hematopoietic-specific subu-nit of WAVE-complex, Hem1, is deleted. By 3 months of age, Hem1-/- mice display lymphopenia, anaemia and extramedullary myelopoiesis, suffer from systemic inflammation and die prematurely. In addition, our preliminary results demonstrate that Hem1-/- mice have developed an aberrant bone-phenotype. Whereas the formation both in vitro and in vivo of Hem1-deficient osteoclasts seems to be promoted, their ability to degrade bone matrix is impaired. Based on these findings, combined with the observation that there is an increase in expression of Hem1 in chronic destructive arthritis, we want to study how Hem1 mediates osteoclast differentiation and bone destruktion and whether it plays a role in rheumatoid arthritis (RA) pathogenesis. In particular, we want to follow the hypothesis that the increased expression of Hem1 in arthritic joints is associated with bone destruction during chronic inflammatory arthritis. Moreover, we want to determine to which extent the loss of Hem1 specifically in osteoclasts or in macrophages affects arthritis development in mice. For this pur-pose, we will induce arthritis in total, macrophage-specific and osteoclast-specific Hem1-/- mice by crossing them into hTNFtg mice, that develop a TNFalpha-dependent arthritis, or by K/BxN serum transfer and analyse the development and severity of disease (e.g. inflammation, synovial hyper-plasia, bone erosion) by morphometric, histological and immunohistochemical methods. Further-more, the putative inhibitory effect of Hem1 on osteoclast differentiation and/or osteoclast cell-fusion will be examined. This project will provide new insights into the mechanisms of inflammatory bone destruction and facilitate the development of novel treatment strategies for chronic inflammatory disorders, particularly RA.

• DFG Programme: Research Grants