Notopterol Attenuates Estrogen Deficiency-Induced Osteoporosis via Repressing RANKL Signaling and Reactive Oxygen Species

Abstract

Integrity of the skeleton is sustained through the balanced activities of osteoblasts and osteoclasts in bone remodeling unit. The balance can be disrupted by excessive osteoclasts activation commonly seen in osteoporosis. Notopterol (NOT) is a main component of Notopterygium incisum which exerts a wide spectrum effect on biomedical pharmacology. In our study, we found NOT serves as an inhibitor in regulating RANKL-activated osteoclasts formation and bone resorption function by calculating tartrate resistant acid phosphatase (TRAcP) staining and hydroxyapatite resorption assays. Furthermore, RANKL-mediated signaling pathways including MAPK, NF-κB and calcium ossification were hampered, whereas ROS scavenging enzymes in Nrf2/Keap1/ARE signaling pathways were promoted by NOT. In addition, the activation of the essential transcription factor NFATc1 in RANKL-mediated osteoclastogenesis was almost totally suppressed by NOT. What is more, NOT diminished the loss of bone mass in preclinical model of OVX mice by blocking osteoclastogenesis determined by bone histomorphometry, TRAcP staining and H&E staining. Conclusively, our findings demonstrated that NOT could arrest osteoclastogenesis and bone resorptive activity by attenuating RANKL-mediated MAPK, NF-κB, calcium and NFATc1 signaling transduction pathways and enhancing ROS scavenging enzymes in Nrf2/Keap1/ARE pathways in vitro, and prohibit bone loss induced by OVX in vivo. Taken together, NOT may be identified to be a natural and novel treatment for osteolytic diseases.

Plasma metabolomic characterization of premature ovarian insufficiency

“…On the one hand, evidence suggested that various ROS triggers could impair ovarian function and that some antioxidants, such as melatonin and resveratrol, could ameliorate excess ROS-induced damage, indicating that excessive oxidative stress may result in the incidence of POI [ 38 ]. On the other hand, oestrogen deficiency as a result of POI is associated with increased oxidative stress, inducing cardiac dysfunction and osteoporosis [ 39 , 40 ]. To determine the causality between the metabolomics changes and POI, further prospective cohort studies are needed.…”

Application of Ginsenoside Rd in Periodontitis With Inhibitory Effects on Pathogenicity, Inflammation, and Bone Resorption

“…A total of 100-μM Rd inhibited osteoclastogenesis of not only RAW264.7 cells, a mice preosteoclastic cell line, but also mice BMDMs treated with RANKL and M-CSF, as shown by the dramatic reduction in the amount and volume of TRAP(+) osteoclasts. TRAP is an extracellular enzyme encoded by Acp5 gene that is commonly utilized to identify osteoclasts, while metalloproteinase (MMP)-9 is vital in mature osteoclasts to mediate bone resorption ( Gu et al., 2014 ; Chen et al., 2021 ). Nuclear factor of activated T cells (NFAT) c1 is one of the main transcription factors in osteoclastogenesis, which could promote the expression of Acp5 and Mmp9 genes ( Egusa et al., 2011 ; Deng et al., 2022 ).…”

Receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis signaling pathway and related therapeutic natural compounds

“…They are beneficial by acting as intracellular signaling factors and detrimental as increasing with age, inflammatory state or age-related diseases ( Go and Jones, 2017 ). Excess ROS destroy bone by reducing the level of antioxidant enzymes and preventing the differentiation of OBs and the formation of OCs ( Chen et al, 2021 ). During the differentiation in osteoclasts, RANKL binds to the receptor RANK, which activates TRAF6 to drive multiple downstream targets.…”