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.

Pathological osteolysis is commonly associated with osteoporosis, bone tumors, osteonecrosis, and chronic inflammation. It involves excessive resorption of bone matrix by activated osteoclasts. Suppressing receptor activator of NF-κB ligand (RANKL) signaling pathways has been proposed to be a good target for inhibiting osteoclast differentiation and bone resorption. Bajijiasu—a natural compound derived from Morinda officinalis F. C. How—has previously been shown to have anti-oxidative stress property; however, its effect and molecular mechanism of action on osteoclastogenesis and bone resorption remains unclear. In the present study, we found that Bajijiasu dose-dependently inhibited RANKL-induced osteoclast formation and bone resorption from 0.1 mM, and reached half maximal inhibitory effects (IC₅₀) at 0.4 mM without toxicity. Expression of RANKL-induced osteoclast specific marker genes including cathepsin K (Ctsk), nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAcP), vacuolar-type H⁺-ATPase V0 subunit D2 (V-ATPase d2), and (matrix metalloproteinase-2 (MMP2) was inhibited by Bajijiasu treatment. Luciferase reporter gene studies showed that Bajijiasu could significantly reduce the expression and transcriptional activity of NFAT as well as RANKL-induced NF-κB activation in a dose-dependent manner. Further, Bajijiasu was found to decrease the RANKL-induced phosphorylation of extracellular signal-regulated kinases (ERK), inhibitor of κB-α (IκB-α), NFAT, and V-ATPase d2. Taken together, this study revealed Bajijiasu could attenuate osteoclast formation and bone resorption by mediating RANKL signaling pathways, indicative of a potential effect of Bajijiasu on osteolytic bone diseases.

Osteonecrosis of femoral head (ONFH) is a disabling clinical entity affecting mainly young adults. Although Chinese Herbal Medicine (CHM) has been widely used as an adjunct therapy for ONFH in China, its effectiveness is not well defined. The purpose of this systematic review is to assess the effectiveness of CHM as an adjunct therapy to core decompression (CD) for patients with ONFH. A systematic literature search was conducted in 10 electronic databases. Randomized controlled trials involving CHM and CD for ONFH were included. Two authors independently assessed the studies for inclusion and extracted the data. A meta-analysis was conducted to estimate the safety and efficacy of CHM as an adjunct therapy. Twenty-three randomized controlled trials with 1815 participants were included. The formulas used in these studies were different and we only combined data of studies observing the same formulas. Patients treated with CHM additionally exhibited a better TER (total effective rate) compared with CD alone in different degree, with the risk ratio (RR) varies from 1.09 to 1.09. The Harris score and radiographic effective rate indicate a similar result, with the medicine (MD) varies from 17.35 to 14.94 and RR 1.40 to 1.27. The risk of side-effect was barely reported except only 2 study record that no complications were observed. This systematic review indicated that CHM as adjunctive therapy may improve the effectiveness of CD. However, a firm conclusion could not be reached because of overall high risk of bias in most domains. Further studies of higher quality are required, and other benefits of CHM remain to be determined.

Iron overload (IO) was considered to be a risk factor for cartilage degradation in knee osteoarthritis (KOA) advancement. However, few drugs were found to improve cartilage degeneration by alleviating multiple cell death induced by the impaired iron level of the knee joints. We aimed to elucidate that Arctiin (ARC) plays a role in managing KOA caused by accumulated iron levels by restoring chondrocyte apoptosis and ferroptosis. Single-cell RNA sequencing analysis was used to discover the disparities in chondrocytes between KOA patients and non-KOA individuals. CCK-8 assay was performed to detect chondrocyte viability. Annexin V-FITC/PI staining determined the cell apoptosis rate. The fluorescence density reflected the iron content, ROS, lipid-ROS, and mitochondrial membrane potential. Q-RTPCR and Western Blotting were used to detect the expression levels of genes and proteins expression. Micro-CT and Safranin O-Fast Green staining were used to detect the phenotype of the knee joints. ARC increased cell viability and inhibited chondrocyte apoptosis. Further, ARC acts as an anti-ferroptosis effect by reducing the intracellular iron, ROS, and lipid-ROS content and restoring mitochondrial damage. Based on the results of scRNA-seq, we found that ARC can play a role by activating AKT/NRF2/HO-1 signaling pathway. In vivo, ARC can significantly improve the severity of KOA caused by IO. ARC alleviates oxidative stress in chondrocytes via the AKT/NRF2/HO-1 signaling pathway, suggesting the potential application of ARC in KOA.