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Excessive bone resorption by osteoclasts (OCs) plays an important role in lytic bone diseases, such as osteoporosis. Although the pharmacological treatment of osteoporosis has been extensively developed, alternative treatments are still needed. Deguelin, a rotenoid isolated from several plant species, is a strong antitumor agent; however, its effect on OCs remains unclear. To the best of our knowledge, this is the first study to report that deguelin inhibits the receptor activator of nuclear factor‐κB (NF‐κB) ligand (RANKL)‐induced osteoclastogenesis, messenger RNA expression of osteoclastic‐specific genes, and osteoclastic bone resorption, in primary bone marrow‐derived macrophages. At the molecular level, deguelin markedly blocked RANKL‐induced osteoclastogenesis by attenuating the phosphorylation of NF‐κB p65 and inhibiting p65 nuclear translocation. In addition, deguelin suppressed the downstream expression of nuclear factor of activated T‐cell cytoplasmic 1, which is a crucial transcription factor in OC differentiation. Consistent with the in vitro results, deguelin inhibited lipopolysaccharide‐induced bone resorption by suppressing osteoclastogenesis. Taken together, our findings reveal that deguelin has antiosteoclastic effects in vitro and in vivo and possesses potential as a new therapeutic option for osteolytic bone diseases. Deguelin suppresses osteoclast formation and function in vitro. Deguelin impairs the receptor activator of nuclear factor‐κB (NF‐κB) ligand (RANKL)‐induced NF‐κB signaling pathway. Deguelin suppresses osteolysis in vivo. Deguelin may be used for treating osteoclast‐related diseases. [ABSTRACT FROM AUTHOR]

Osteoporosis is a metabolic bone loss disorder usually accompanied by overactivated osteoclast formation and increased bone resorption. Transcriptional co-activator with PDZ-binding motif (TAZ) is an emerging potential target for the treatment of osteoporosis. Our previous research showed that TAZ overexpression inhibited osteoclast formation while TAZ silencing had the opposite effect. In addition, TAZ knockout in mouse osteoclasts induced osteoporosis in animal experiments. XMU-MP-1 (XMU) is a selective MST1/2 inhibitor that can theoretically activate TAZ; however, its effect on osteoporosis remains unknown. In this study, we found that XMU treatment significantly increased TAZ expression in osteoclasts and inhibited osteoclast formation in vitro ; however, this inhibitory effect was eliminated after the deletion of TAZ. Furthermore, XMU treatment upregulated TAZ expression in osteoclasts and alleviated ovariectomy (OVX)-induced osteoporosis in bilateral OVX mouse models. These findings suggest that XMU can effectively activate TAZ and that pharmacological activation of TAZ may be a promising option for the treatment of osteoporosis. • XMU treatment significantly increased TAZ expression in osteoclasts. • XMU treatment inhibited osteoclast formation in vitro via TAZ. • XMU treatment alleviated ovariectomy-induced osteoporosis in mouse models. [ABSTRACT FROM AUTHOR]

[Display omitted] Excessive osteoclast activation is a leading cause of osteoporosis. Therefore, identifying molecular targets and relevant pharmaceuticals that inhibit osteoclastogenesis is of substantial clinical importance. Prior research has indicated that transcriptional coactivator with PDZ-binding motif (TAZ) impedes the process of osteoclastogenesis by engaging the nuclear factor (NF)-κB signaling pathway, thereby suggesting TAZ activation as a potential therapeutic approach to treat osteoporosis. (R)-PFI-2 is a novel selective inhibitor of SETD7 methyltransferase activity, which prevents the nuclear translocation of YAP, a homolog of TAZ. Therefore, we hypothesized that (R)-PFI-2 could be an effective therapeutic agent in the treatment of osteoporosis. To test this hypothesis and explore the underlying mechanism, we first examined the impact of (R)-PFI-2 on osteoclastogenesis in bone marrow macrophages (BMMs) in vitro. (R)-PFI-2 treatment inhibited TAZ phosphorylation induced by NF-κB, thereby enhancing its nuclear localization, protein expression, and activation in BMMs. Moreover, (R)-PFI-2-induced TAZ activation inhibited osteoclast formation in a dose-dependent manner, which involved inhibition of osteoclastogenesis through the TAZ and downstream NF-κB pathways. Furthermore, (R)-PFI-2 inhibited osteoclastogenesis and prevented ovariectomy-induced bone loss in vivo in a mouse model. Overall, our findings suggest that TAZ activation by (R)-PFI-2 inhibits osteoclastogenesis and prevents osteoporosis, indicating an effective strategy for treating osteoclast-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Osteolytic diseases are characterized by an increase in the number and/or activity of bone‐resorbing osteoclasts. Identification of natural compounds that can suppress osteoclast formation and function is crucial for the prevention and treatment of osteolytic diseases. Vitexin, a naturally‐derived flavonoid extracted from various medicinal plant species, demonstrates a broad range of pharmacological properties including anticancer and anti‐inflammatory effects. Here in this study, we showed that vitexin exerts antiosteoclastogenic effects by directly inhibiting receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast formation and bone resorption in vitro and protected against lipopolysaccharide (LPS)‐induced inflammatory osteolysis in vivo. Vitexin suppressed the early activation of ERK and p38 MAPK pathways in response to RANKL thereby attenuating the downstream induction of c‐Fos and NFATc1, and abrogating the expression of osteoclast marker genes. Collectively, these results provide evidence for the therapeutic application of vitexin in the treatment of osteoclast‐mediated bone lytic diseases. [ABSTRACT FROM AUTHOR]

Osteoclasts (OCs) are multinuclear giant cells responsible for bone resorption, and an excessive bone resorption by OCs plays an important role in osteoporosis. Commonly used drugs for the treatment of osteoporosis have severe side effects. As such, identification of alternative treatments is essential. Garcinol, a polyisoprenylated benzophenone extracted from the fruit of Garcinia indica, has shown a strong antitumor effect through the nuclear factor‐κB (NF‐κB) and mitogen‐associated protein kinases (MAPK) signaling pathways. However, the role of garcinol in the osteoclastogenesis is still unclear. Here, we demonstrated that garcinol can inhibit the receptor activator of NF‐κB ligand (RANKL)‐induced osteoclastogenesis, osteoclastogenesis‐related gene expression, the f‐actin ring, and resorption pit formation. In addition, garcinol abrogated RANKL‐induced osteoclastogenesis by attenuating the degradation of the MAPK, NF‐κB, and PI3K‐AKT signaling pathway as well as downstream factors c‐jun, c‐fos, and NFATC1. In vivo, suppression of osteoclastogenesis by garcinol was evidenced by marked inhibition of lipopolysaccharide‐induced bone resorption. In conclusion, our data demonstrated that garcinol inhibited the RANKL‐induced osteoclastogenesis by suppressing the MAPK, NF‐κB, and PI3K‐AKT signaling pathways and thus has potential as a novel therapeutic option for osteolytic bone diseases. Garcinol suppresses osteoclast (OCs) formation and function in vitro. Garcinol impairs the receptor activator for the nuclear factor‐κB ligand (RANKL)‐induced mitogen‐associated protein kinases (MAPK), nuclear factor‐κB (NF‐κB), and AKT signaling pathway. Garcinol suppresses osteolysis in vivo. Garcinol may be a new therapeutic option for osteolytic bone diseases [ABSTRACT FROM AUTHOR]

• Hinokitiol lowered RANKL-induced osteoclast formation and bone resorption in vitro. • Hinokitiol inhibited early activation of the ERK, p38, and JNK–MAPK pathways. • Hinokitiol also suppressed the activity and expression of c‐Jun, c‐Fos, and NFATC1. • Hinokitiol treatment protected against ovariectomy-induced bone loss in vivo. • Hinokitiol has potential as a novel treatment for osteoclast-induced osteoporosis. Osteoporosis is a metabolic bone-loss disease characterized by abnormally excessive osteoclast formation and bone resorption. Identification of natural medicines that can inhibit osteoclastogenesis, bone resorption, and receptor activator of nuclear factor-κB ligand (RANKL)‐induced signaling is necessary for improved treatment of osteoporosis. In this study, hinokitiol, a tropolone-related compound extracted from the heart wood of several cupressaceous plants, was found to inhibit RANKL-induced osteoclast formation and bone resorption in vitro. Hinokitiol inhibited early activation of the ERK, p38, and JNK–MAPK pathways, thereby suppressing the activity and expression of downstream factors (c‐Jun, c‐Fos, and NFATC1). Consistent with the above in vitro findings, hinokitiol treatment protected against ovariectomy-induced bone loss in vivo. Collectively, our results imply that hinokitiol can potentially serve as an effective agent for treating osteoclast-induced osteoporosis. [ABSTRACT FROM AUTHOR]