Mechanisms involved in enhancement of osteoclast formation by activin‐A

Abstract

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.

The effect of Activin‐A on periodontal ligament fibroblasts‐mediated osteoclast formation in healthy donors and in patients with fibrodysplasia ossificans progressiva

“…The effect of Activin-A on osteoclast formation and activity has thus far only been investigated in murine cells, and shows contradictory results, partly owing to the used population of osteoclast precursors. An enhanced osteoclast formation and activity was found in several studies using mouse total bone marrow or RAW264.7 cells as the source of osteoclast precursors(Fowler et al, 2015;Fuller et al, 2000;Gaddy-Kurten, Coker, Abe, Jilka, & Manolagas, 2002;Kajita et al, 2018). However,Fowler et al (2015) using bone marrow macrophages, showed a decrease in osteoclast formation due to decreased motility of the precursors as well as a decrease in osteoclast activity due to lower Cathepsin K expression and higher apoptosis.…”

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

“… Crosstalk between TGF-β superfamily signaling and M-CSF/RANKL pathways to regulate osteoclast differentiation and function [ 59 , 184 , 325 ]. CTR: Calcitonin receptor; DC-STAMP: Dendritic cell–specific transmembrane protein; MMP: Matrix metalloproteinase; OC-STAMP: Osteoclast Stimulatory Transmembrane Protein; and TRAP: Tartrate-resistant acid phosphatase.…”

Elimination of unfit cells in young and ageing skin

“…The maintenance of fit stem cells through the years in which an individual is likely to reproduce probably also prevents tumour development, because these fit cells compete with (and eliminate) both damaged stem cells and tumour-prone cells 7 . Notably, cell competition has previously been shown to promote the expulsion from the epithelium of cells with tumour-causing mutations or other abnormal features 8,9 .…”