Spi-C positively regulates RANKL-mediated osteoclast differentiation and function

Abstract

Spi-C is an SPI-group erythroblast transformation-specific domain transcription factor expressed during B-cell development. Here, we report that Spi-C is a novel receptor activator of nuclear factor-κB ligand (RANKL)-inducible protein that positively regulates RANKL-mediated osteoclast differentiation and function. Knockdown of Spi-C decreased the expression of RANKL-induced nuclear factor of activated T-cells, cytoplasmic 1, receptor activator of nuclear factor-κB (RANK), and tartrate-resistant acid phosphatase (TRAP), resulting in a marked decrease in the number of TRAP-positive multinucleated cells. Spi-C-transduced bone marrow-derived monocytes/macrophages (BMMs) displayed a significant increase in osteoclast formation in the presence of RANKL. In addition, Spi-C-depleted cells failed to show actin ring formation or bone resorption owing to a marked reduction in the expression of RANKL-mediated dendritic cell-specific transmembrane protein and the d2 isoform of vacuolar (H+) ATPase V0 domain, which are known osteoclast fusion-related genes. Interestingly, RANKL stimulation induced the translocation of Spi-C from the cytoplasm into the nucleus during osteoclastogenesis, which was specifically blocked by inhibitors of p38 mitogen-activated protein kinase (MAPK) or PI3 kinase. Moreover, Spi-C depletion prevented RANKL-induced MAPK activation and the degradation of inhibitor of κB-α (IκBα) in BMMs. Collectively, these results suggest that Spi-C is a novel positive regulator that promotes both osteoclast differentiation and function.

EP3 enhances adhesion and cytotoxicity of NK cells toward hepatic stellate cells in a murine liver fibrosis model

“…Spic, a PU.1-related TF, controls the development of red pulp macrophages ( Kohyama et al, 2009 ), B cells ( Laramee et al, 2020 ), and osteoclasts ( Go et al, 2020 ), partially by upregulation of adhesion genes such as integrin αM and αD ( Haldar et al, 2014 ; Okreglicka et al, 2021 ). Deletion of EP3 caused functional defects in adhesion and cytolysis in DP NK cells through reducing the activity of Spic, which also interrupts development of NK cells ( Kohyama et al, 2009 ).…”

Green Tomato Extract Prevents Bone Loss in Ovariectomized Rats, a Model of Osteoporosis

“…Nox-4 is a notable gene induced during the osteoclastogenesis process. The loss of Nox-4 activity halts the osteoclastogenesis process and favors the bone formation process [ 33 , 34 ]. The present observation of lowered Nox-4 expression demonstrated that the total osteoclastogenesis process was suspended in GTE supplemented OVX rats.…”

Efficacy assessment of methylcellulose-based thermoresponsive hydrogels loaded with gallium acetylacetonate in osteoclastic bone resorption

“…The next day, the wells were aspirated and replenished with media containing RANKL; this was repeated for the next 2 days. On day 10, the wells were aspirated and the bone chips were fixed and stained, as reported previously [ 49 ].…”