Abstract
Inflammatory osteolysis is a pathological skeletal disease associated with not only the production of inflammatory cytokines but also local oxidative status. Excessive reactive oxygen species (ROS) promote bone resorption by osteoclasts and induce the apoptosis of osteoblasts. In consideration of the lack of effective preventive or treatments options against osteolysis, the exploitation of novel pharmacological compounds/agents is critically required. In our study, we found that a novel antioxidant compound, JSH-23, plays a role in restoring bone homeostasis by scavenging intracellular ROS during both osteoclastogenesis and osteoblastogenesis. Mechanically, JSH-23 suppressed RANKL-induced osteoclastogenesis, bone resorption and the expression of specific genes (including NFATc1, c-Fos, TRAP, CTSK and DC-STAMP) via inhibition of the NF-κB signaling pathway. Meanwhile, JSH-23 suppressed RANKL-induced ROS generation via the TRAF6/Rac1/NOX1 pathway and the enhanced expression of Nrf2/HO-1. In addition, JSH-23 attenuated H2O2-induced apoptosis and mineralization reduction in osteoblasts by reducing ROS production and enhancing Nrf2/HO-1 expression. Our in vivo results further revealed that JSH-23 exerts its protective effects on bone mass through its antioxidant activity. In conclusion, our results show that the application of JSH-23 might be a novel and plausible strategy for the treatment of osteolysis-related disease.
Highlights
Inflammatory osteolytic diseases, including rheumatoid arthritis, periodontitis and osteomyelitis, is characterized by an imbalance in bone remodeling triggered by an increased number of osteoclasts in conjunction with a decreased in the bone formation ability of osteoblasts, leading to pathological bone destruction (Jimi et al, 2004; Smolen et al, 2016; Wang et al, 2021)
tartrate-resistant acid phosphatase (TRAP) staining showed that JSH-23 suppressed the total number of cells undergoing osteoclastogenesis and the area of RANKLinduced osteoclastogenesis in a dose-dependent manner (Figures 1C,D)
After downregulation of nuclear factor E2-related factor 2 (Nrf2) or heme oxygenase 1 (HO-1), the protective effect of JSH-23 against the H2O2induced reductions in the levels of osteoblast markers (Runx2, OCN and BMP2) was attenuated (Figures 7K,L). These results suggest that JSH-23 prevents H2O2-induced impairment of osteoblast differentiation by scavenging intracellular reactive oxygen species (ROS) and increasing activation of the Nrf2/HO-1 pathway
Summary
Inflammatory osteolytic diseases, including rheumatoid arthritis, periodontitis and osteomyelitis, is characterized by an imbalance in bone remodeling triggered by an increased number of osteoclasts in conjunction with a decreased in the bone formation ability of osteoblasts, leading to pathological bone destruction (Jimi et al, 2004; Smolen et al, 2016; Wang et al, 2021). Local inflammation in the bone induces the production of pro-osteoclastogenic cytokines, including tumor necrosis factor-α (TNF-α) and interleukins (ILs), which promote the differentiation and activation of bone-resorbing osteoclasts by increasing the expression of receptor activator of nuclear factor κB. During RANKL-induced osteoclast formation, ROS maintain their normal functions in differentiation, survival, activation and bone resorption (Ashtar et al, 2020). They can reduce osteoblast formation by inducing osteoblast apoptosis and decreasing osteoblast activity (Han et al, 2019). Limiting the excessive production of intracellular ROS has been assumed to prevent the extreme formation of osteoclasts and apoptosis of osteoblasts induced by local inflammation (Bodega et al, 2019; Tao et al, 2020)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
