The role of myostatin in joint destruction in rheumatoid arthritis

• Applicant: Berno Dankbar, Ph.D.
• Subject Area: Rheumatology
• Term: from 2010 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 169271848

Myostatin (GDF-8) is a member of the transforming growth factor-( (TGF-() family that is expressed in skeletal muscle and serves as a negative regulator of muscle growth. Recent findings indicate that myostatin may also play a role in regulating bone development and that inhibition of myostatin may diminish bone resorption and improve bone formation. Based on own preliminary results demonstrating a disease-specific expression of myostatin in chronic destructive arthritis and a potentiating effect on RANKL- induced osteoclastogenesis, we want to study whether myostatin plays a role in the pathogenesis of RA. In particular, we want to follow the hypothesis that the expression of myostatin in arthritic joints is associated with an enhanced osteoclast formation and thus, significantly involved in bone destruction during chronic inflammatory arthritis. For this purpose, we will cross the Mstn-knockout mice into hTNFtg mice that develop a TNF-alpha dependent arthritis and analyze the development and severity of disease (e.g. inflammation, synovial hyperplasia, bone erosion) by morphometric, histological and immunohistochemical methods. Further experiments on signal transduction pathways involved in the myostatinboosted osteoclast formation as well as in the regulation of myostatin itself will provide starting points for the inhibition of this potent osteoclastogenic factor. 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: Priority Programmes
• Subproject of: SPP 1468: Osteoimmunology - IMMUNOBONE - A Programme to Unravel the Mutual Interactions between the Immune System and Bone
• Participating Person: Professor Dr. Thomas Pap