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Mechanisms involved in enhancement of osteoclast formation by activin‐A
Author(s) -
Kajita Tomonari,
Ariyoshi Wataru,
Okinaga Toshinori,
Mitsugi Sho,
Tominaga Kazuhiro,
Nishihara Tatsuji
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26906
Subject(s) - activin type 2 receptors , rankl , osteoclast , acvr2b , microbiology and biotechnology , chemistry , rank ligand , medicine , signal transduction , endocrinology , transforming growth factor , activator (genetics) , biology , receptor , tgf beta signaling pathway , biochemistry
Several growth factors in bone tissues are reported to be associated with osteoclastogenesis. Activin‐A, a member of the transforming growth factor‐β (TGF‐β) family is known to be present in bone tissues and an important regulator in osteoclastogenesis with SMAD‐mediated signaling being crucial for inducing osteoclast differentiation. In the present study, we examined the effect and underlying mechanisms of activin‐A on osteoclast formation in vitro culture systems. Activin‐A enhanced osteoclast formation in both mouse bone marrow cells and monocyte/macrophage cell line RAW 264.7 cells induced by receptor activator of nuclear factor kappa B (NF‐κB) ligand (RANKL) and/or macrophage stimulating factor (M‐CSF). We also found that activin‐A stimulated bone resorption and actin ring formation induced by RANKL and/or M‐CSF. Furthermore, activin‐A enhanced RANKL‐induced expression of nuclear factor of activated T cell cytoplasmic 1 (NFATc1), a key regulator of osteoclastogenesis, thereby increasing osteoclastogenesis‐related marker gene expression, including tartrate‐resistant acid phosphatase, osteoclast stimulatory transmembrane protein, and cathepsin K. Blockage of receptor binding by follistatin, an activing‐binding protein suppressed the activin‐A‐mediated stimulation of NFATc1. In addition, activin‐A increased RANKL‐induced c‐fos expression without significantly affecting the NF‐κB and mitogen‐activated protein kinase (MAPK) signaling pathway. Pre‐treatment of the cells with a specific inhibitor of SMAD2/3 attenuated the activin‐A‐induced expression of NFATc1 and co‐immunoprecipitation assay revealed that treatment with activin‐A increased physical interaction of phosphorylated‐c‐fos and phosphorylated‐SMAD2 protein induced by RANKL. These results suggest that activin‐A enhances RANKL‐induced osteoclast formation mediated by interaction of c‐fos and smad2/3.