Abstract
Inflammatory bone diseases, including rheumatoid arthritis, periodontitis and peri-implantitis, are associated not only with the production of inflammatory cytokines but also with local oxidative status, which is defined by intracellular reactive oxygen species (ROS). Osteoclast differentiation has been reported to be related to increased intracellular ROS levels in osteoclast lineage cells. Sudachitin, which is a polymethoxyflavone derived from Citrus sudachi, possesses antioxidant properties and regulates various functions in mammalian cells. However, the effects of sudachitin on inflammatory bone destruction and osteoclastogenesis remain unknown. In calvaria inflamed by a local lipopolysaccharide (LPS) injection, inflammation-induced bone destruction and the accompanying elevated expression of osteoclastogenesis-related genes were reduced by the co-administration of sudachitin and LPS. Moreover, sudachitin inhibited osteoclast formation in cultures of isolated osteoblasts and osteoclast precursors. However, sudachitin rather increased the expression of receptor activator of NF-κB ligand (RANKL), which is an important molecule triggering osteoclast differentiation, and the mRNA ratio of RANKL/osteoprotegerin that is a decoy receptor for RANKL, in the isolated osteoblasts, suggesting the presence of additional target cells. When osteoclast formation was induced from osteoclast precursors derived from bone marrow cells in the presence of soluble RANKL and macrophage colony-stimulating factor, sudachitin inhibited osteoclastogenesis without influencing cell viability. Consistently, the expression of osteoclast differentiation-related molecules including c-fos, NFATc1, cathepsin K and osteoclast fusion proteins such as DC-STAMP and Atp6v0d2 was reduced by sudachitin. In addition, sudachitin decreased activation of MAPKs such as Erk and JNK and the ROS production evoked by RANKL in osteoclast lineage cells. Our findings suggest that sudachitin is a useful agent for the treatment of anti-inflammatory bone destruction.
Highlights
Osteoclasts are the cells responsible for physiological and pathological bone resorption and belong to the monocyte/macrophage cell lineage [1]
Sudachitin repressed the activation of Erk and JNK, which are pivotal signaling pathways for osteoclast differentiation, while simultaneously decreasing intracellular reactive oxygen species (ROS) production
To examine the mechanism underlying the inhibitory effect of sudachitin on osteoclast formation in the co-culture, we examined the mRNA expression levels of RANKL, which is a molecule that triggers osteoclast differentiation, and OPG, which is an anti-osteoclast differentiation cytokine, in isolated osteoblasts (Fig 2C–2E)
Summary
Osteoclasts are the cells responsible for physiological and pathological bone resorption and belong to the monocyte/macrophage cell lineage [1]. Many systemic hormones and local cytokines regulate osteoclast differentiation [2], the receptor activator of NF-κB (RANK) ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are the most important molecules in osteoclastogenesis. The signals of RANKL that is produced by bone marrow stromal cells or osteoblasts are introduced into osteoclast precursors, via a receptor of RANKL (RANK) on the plasma membrane of osteoclast lineage cells, leading to the activation of NF-κB and MAPKs [3,4,5,6,7,8]. Local inflammation in bone induces the production of pro-osteoclastogenic cytokines, including RANKL, tumor necrosis factor-α (TNF-α) and interleukins (ILs), such as IL-1β and IL-17 [16]. ROS can act as signaling transduction molecules involved in the regulation of many cellular events, such as angiogenesis, myogenesis and adipogenesis [19,20,21]
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