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.
Highlights
Osteoclasts are multinucleated giant cells that can resorb bone
The same was true in response to RANKL treatment for 3 or 5 days, in which RANKL stimulation notably induced the expression of Spi-C in a timedependent manner (Fig. 1c)
As Spi-C overexpression significantly increased the formation of large tartrate-resistant acid phosphatase (TRAP)+multinucleated cells (MNCs) (Fig. 2e, g), we further investigated whether Spi-C regulates the expression of the DC-STAMP and Atp6v0d2 genes, which are known to be related to osteoclast fusion
Summary
Osteoclasts are multinucleated giant cells that can resorb bone. They induce skeletal development and continuous bone remodeling together with bone-forming osteoblasts[1,2]. Osteoclast precursors are derived from hematopoietic progenitors of the monocyte/macrophage lineage. Receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (MCSF) are essential for osteoclast differentiation[3,4]. Excess osteoclast activity results in bone loss, as observed in various bone-related diseases, including postmenopausal osteoporosis[5,6,7]. Studies of the regulatory mechanisms of osteoclast differentiation and function are
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