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

Dankbar B, et al. Nat Med. 2015; 21(9):1085-90.

Speaker: Guan-Yu Chen (陳冠宇)                                                Time: 15:00~16:00, Feb 24, 2016

Commentator: Dr. Chrong-Reen Wang (王崇任醫師)         Place: Room 601

Abstract:

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease primarily affecting the joints, leading to progressive bone destruction. Myostatin (also known as growth and differentiation factor 8, GDF8) is a member of the transforming growth factor-β (TGF-β) family. Lack of myostatin has been shown to increase bone formation [1]. In this study, the authors investigated whether myostatin plays a role in bone resorption and RA pathology. The authors demonstrated that the synovial tissues of patients with RA expressed higher levels of myostatin compared to those with osteoarthritis. Myostatin enhanced receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis of osteoclast precursors. Numbers of RANKL-induced osteoclasts were also reduced in myostatin gene deficient mice (Mstn^-/-) compared to wild-type mice. To study whether loss of myostatin can ameliorate bone erosion during inflammatory arthritis, the authors crossed human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, a model for human RA, with Mstn^-/- mice, and demonstrated that the levels of joint destruction were significantly reduced in hTNFtg;Mstn^-/- mice compared to hTNFtg mice. Myostatin regulated nuclear factor of activated T-cells (NFATC1) through SMAD2 to induce osteoclast formation. In summary, these results suggest that myostatin may be a therapeutic target for joint destruction in RA.

Reference:

1.     Hamrick MW. Increased bone mineral density in the femora of GDF8 knockout mice. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 2003; 272:388-91.