Avicularin Alleviates Osteoporosis in Ovariectomized Mice by Inhibiting Osteoclastogenesis through NF-κB Pathway Inhibition

Abstract

Osteoporosis (OP) is mainly manifested by bone loss and bone degeneration. OP is considered a risk factor for pathological fractures, as well as impacts the health of middle-aged and elderly individuals. Drug therapy remains the main treatment scheme for OP; however, its efficacy is limited and has been associated with serious side effects. Therefore, it is important to develop new, effective, and safe treatment methods for OP. Avicularin (AL) is a flavonoid and quercetin derivative from various plants. Our study showed that AL disrupts osteoclast activation and resorptive function via inhibition of the RANKL-induced osteoclast differentiation together with the resorption capacity of bone marrow-derived macrophages (BMMs). Hence, AL prevents the activation and resorptive activity of osteoclasts. The results of qPCR showed that genes related to osteoclasts exhibited downregulated expression after AL treatment. Furthermore, AL inhibited RANKL-induced phosphorylation as well as degradation of the inhibitor IκBα of the NF-κB pathway, together with P65 phosphorylation in BMMs. We used an OP mouse model that was established by ovariectomy (OVX). Relative to untreated OP mice, mice that received AL treatment showed a significant increase in bone mineral density; however, the expression of TRAP, NFATC1, mmp9, and CTX-1 was significantly reduced. These results indicate that AL disrupts osteoclastogenesis via inhibition of the NF-κB pathway, which in turn improves OVX-induced OP.

Garcinone C attenuates RANKL-induced osteoclast differentiation and oxidative stress by activating Nrf2/HO-1 and inhibiting the NF-kB signaling pathway

“…In RANKL knockout mice [ 43 ], NF-κB can promote osteoclastogenesis by activating the RANKL/RANK pathway [ 44 ]. Blocking NF-κB signaling is thought to be an effective way to prevent osteoclast activity [ 21 , 22 , 45 ]. Nrf2 is a redox-sensitive transcription factor that controls cellular antioxidant defenses by inducing antioxidant gene expression [ 46 ].…”

“…In the OVX group and the OVX + Gar C group, respectively, an incision of about 1.5 cm in length was made in the middle of the lower abdomen of the mice under anesthesia and the incision was sutured after removing the bilateral ovaries and the surrounding adipose tissue. In the Sham group, only the ovaries were exposed, and the surrounding adipose tissue was removed and then incorporated into the abdominal suture to close the incision [ 21 ].The JONN laboratory in Suzhou, China, provided us with 24 experimental C57BL/6 mice (no. 202236274).…”

“…These mice were 6 weeks old and weighed 20 g on average. After 3 weeks, 5 mg/kg Gar C was injected intraperitoneally every 2 days in the OVX + Gar C low-dose group, and 25 mg/kg Gar C was injected intraperitoneally every 2 days in the OVX + Gar C high-dose group, Mice in the sham-operated and OVX groups were injected with the same amount of normal saline [ 21 , 22 ].After 8 weeks, the femur and spine were removed and fixed in 4 % paraformaldehyde ( Fig. 1 ).…”

MiR-137 promotes TLR4/NF-κB pathway activity through targeting KDM4A, inhibits osteogenic differentiation of human bone marrow mesenchymal stem cells and aggravates osteoporosis

“…Especially, the signal transduction pathway of TLR4 can activate NF-κB continuously, thus promoting the transcription of various inflammatory factors and resulting in a cascade of inflammatory responses. NF-κB, a major transcription factor in inflammatory response, regulates the differentiation of both osteoblasts and osteoclasts and maintains bone homeostasis [ 31 ]. Our results showed that miR-137 significantly increased the protein expression levels of TLR4 and p65, which indicates that miR-137 may regulate osteogenic differentiation by activating the TLR4/NF-κB signaling pathway in hBMSCs.…”

Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets

“…Furthermore, Zhu et al found that isopsoralen promoted the differentiation of human jawbone marrow mesenchymal cells into osteoblasts, suggesting its potential in restoring bone formation (Zhu et al 2023 ). Zhuang et al demonstrated that Avicularin (AL), a flavonoid and quercetin derivative, ameliorated osteoporosis by disrupting osteoclast formation through inhibiting the NF-κB pathway (Zhuang et al 2023 ). Huang et al discovered that dictamnine (DIC), a furoquinoline alkaloid, suppressed osteoclast formation, bone resorption, F-actin band formation, and osteoclast-specific gene expression by inhibiting the activity of nuclear factor erythroid2-related factor 2 (Nrf2), promoting the binding of Nrf2 and NF-κB, and blocking NFATc1 expression (Wong et al 2022 ).…”