Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice

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Abstract

Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-β (TGF-β) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene (Mstn) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration1,2,3,4,5. However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone6,7,8,9,10,11. Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, a model for human RA12. Myostatin strongly accelerates receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast formation in vitro through transcription factor SMAD2-dependent regulation of nuclear factor of activated T-cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA.

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Figure 1: High levels of myostatin in synovial tissues of arthritic individuals and mice.
Figure 2: Myostatin directly enhances osteoclast differentiation.
Figure 3: Deficiency or inhibition of myostatin ameliorates joint destruction in hTNFtg mice.
Figure 4: Myostatin enhances expression of key differentiation genes via SMAD2-dependent nuclear translocation of NFATC1.

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Acknowledgements

We thank S.-J. Lee (Johns Hopkins University School of Medicine) for providing us with the Mstn−/− mice, and G. Kollias (Alexander Fleming Biomedical Sciences Research Center) for the hTNF transgenic mice. We also thank Pfizer, Inc. for providing us with the myostatin-specific antibody. We thank X. Lin (Department of Surgery, Baylor College of Medicine) for providing us with the SMAD2 constructs. We thank V. Eckervogt and B. Truckenbrod for excellent technical support. This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; DA 1143/4-1 and DA 1143/4-2 to B.D. and T.P. as part of the Priority Programme SPP 1468, IMMUNOBONE) and by the Collaborative Research Center SFB 1009 granted to T.P.

Author information

B.D. designed and performed all experiments and wrote the manuscript; C.K.-W. and C.W. participated in the histomorphometric analyses; A.S., A.K-P. and P.P. contributed to experimental design and prepared mice and tissues and participated in the antibody experiments; D. Brunert performed the ELISA experiments and prepared mice; S.H. and K.R. conducted the studies with the K/BxN mouse model; S.F. participated in the transfection studies and performed the luciferase assays; M.F., J.B. and D. Beckmann performed the qPCR and the co-culture experiments; and T.P. participated in data analysis, directed the project and wrote the manuscript.

Correspondence to Thomas Pap.

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Dankbar, B., Fennen, M., Brunert, D. et al. Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice. Nat Med 21, 1085–1090 (2015) doi:10.1038/nm.3917

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