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-kappa B 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-kappa B (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 kappa B-alpha (I kappa B alpha) in BMMs. Collectively, these results suggest that Spi-C is a novel positive regulator that promotes both osteoclast differentiation and function. Bone maintenance: regulating cells that break down bone A gene-controlling protein called Spi-C promotes the development of bone-processing cells called osteoclasts; details of the molecular mechanisms involved will aid understanding of Spi-C's role in bone health and disease. Osteoclasts degrade bone during the normal process of bone remodeling, balanced by the activity of osteoblast cells that form new bone. Excessive osteoclast activity can cause the bone loss associated with various bone diseases including early-onset osteoporosis. Researchers in South Korea led by Soo Young Lee at Ewha Womans University and Na Kyung Lee at Soonchunhyang University, Asan, found that Spi-C promotes osteoclast development by activating genes that code for key proteins of a signaling pathway known to be crucial for bone health. Drugs that interfere with Spi-C activity may therefore offer a new approach for treating bone disease.