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Dankbar et al. Could myostatin be developed as a treatment for human RA?
DOI:10.1038/bonekey.2015.132
Myostatin, a secreted protein that belongs to the transforming growth factor-β (TGF-β) family, appears to be a negative regulator of muscle growth and regeneration; it also indirectly stimulates bone formation through enhanced loading. In this study, Dankbar et al. describe a potential role for myostatin in the pathology of rheumatoid arthritis (RA).
In vitro, myostatin appears to activate RANKL-mediated osteoclastogenesis through transcription factor SMAD2-dependent regulation of nuclear factor of activated T-cells (NFATC1).
Analysis of the synovial tissues of patients with RA and of human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, an established animal model of RA, revealed a high level of expression of myostatin. When myostatin deficiency was induced in hTNFtg mice or inhibited by therapy with specific antibody, the mice suffered lower levels of bone destruction compared to controls. In another mouse model of serum-induced arthritis, K/BxN mice that lacked myostatin showed lower levels of bone erosion and an increase in grip strength, again compared to control mice with normal myostatin levels.
Editor’s comment: This provocative study raises several questions. It is not known whether the expression level of myostatin in synovial tissues of RA subjects and model animals is higher than the orthotopic expression in muscles. If myostatin-induced phosphorylation of Smad2 enhances its binding and nuclear translocation of NFATc1, muscle-derived myostatin may also enhance osteoclast formation in bone.
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