Mussaendoside O, a N-triterpene cycloartane saponin, attenuates RANKL-induced osteoclastogenesis and inhibits lipopolysaccharide-induced bone loss

Gal, Minju; Kim, Okwha; Tran, Phuong Thao; Huong, Le Thanh; Nhiệm, Nguyễn Xuân; Kiệm, Phan Văn; Dang, Nguyen Hai; Lee, Jeong‐Hyung

doi:10.1016/j.phymed.2022.154378

Cited by 15 publications

(7 citation statements)

References 28 publications

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“…Afterward, when the NF-κB or MAPK signaling pathway is vitalized, succedent factor c-Fos is phosphorylated to activate osteoclast differentiation (34,59), which plays a critical role as a transcription factor for osteoclast differentiation (39). Transcription factor c-Fos is vital for early induction of NFATc1 (41), an essential transcription factor in osteoclast formation (34,54), and a master regulator indispensable for osteoclast differentiation (41).…”

Section: Discussionmentioning

confidence: 99%

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Chen

Gan

Wang

et al. 2023

Preprint

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Background Numerous studies have confirmed that activated osteoclasts cause excessive bone resorption, disrupting bone homeostasis and leading to osteoporosis. Moreover, ERK signaling is the classical pathway related to osteoclast differentiation. Besides, reactive oxygen species (ROS) is mainly from mitochondria, which is closely associated with the differentiation of osteoclasts. Myrislignan (MRL), a natural product derived from nutmeg, has various pharmacological activities. However, its effect on the treatment of osteoporosis is unclear. Therefore, this study mainly investigated whether MRL could inhibit osteoclastogenesis and bone mass loss in ovariectomy (OVX) mice via suppressing mitochondrial function and ERK signaling.Methods Tartrate-resistant and phosphatase (TRAP) assay and bone resorption assay were used to observe the effect of MRL on osteoclastogenesis. Furthermore, we added MitoSOX RED and tetramethyl rhodamine methyl ester (TMRM) staining to test the inhibitory effect of MRL on mitochondria. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay detected whether MRL suppressed the expression of specific genes in osteoclasts. The impact of MRL on mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) related proteins was evaluated by western blotting. Besides, a specific ERK agonist LM22B-10 (LM), was added to revalidate the inhibitory effect of MRL on ERK. Moreover, we established an OVX mouse model to assess the therapeutic effect of MRL on osteoporosis in vivo.Results MRL was proven to press osteoclast differentiation and bone resorption function, significantly reducing osteoclastic gene expression. Mechanistically, MRL inhibited the phosphorylation of ERK by suppressing the role of mitochondria, causing the downregulation of nuclear factor of activated T cells 1 (NFATc1) signaling. The experiment result of adding LM further clarified the targeted inhibition effect of MRL on ERK. The results of microscopic computed tomography (Micro-CT) and histology sections of the tibia in vivo indicated that OVX mice had lower bone mass and higher expression of ERK. However, after the MRL application, these results were significantly reversed, suggesting that MRL had a decent anti-osteoporosis effect.Conclusion We saw for the first time that MRL could inhibit ERK signaling by suppressing mitochondrial function, thus reducing OVX-induced osteoporosis. This novel finding could provide a broad prospect for the treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Chen

Gan

Wang

et al. 2023

Preprint

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“…Moreover, 30 attenuates LPS-induced bone resorption and osteoclast formation in mice by repressing RANKL-induced activation of p38 MAPK and JNK, preventing c-Fos activation and subsequent expression of NFATc1. Saponin 30 also diminished RANKLinduced increase in mRNA expression of NFATc1 target genes, including OSCAR, TRAP, DC-STAMP and cathepsin K [114].…”

Section: Triterpenic Saponinsmentioning

confidence: 92%

“…Mussaendoside O (30), a N-triterpene cycloartane saponin isolated from Mussaenda pubescens, inhibits RANKL-induced osteoclastogenesis in vitro in a concentration-dependent manner [114]. Moreover, 30 attenuates LPS-induced bone resorption and osteoclast formation in mice by repressing RANKL-induced activation of p38 MAPK and JNK, preventing c-Fos activation and subsequent expression of NFATc1.…”

Section: Triterpenic Saponinsmentioning

confidence: 99%

“…NF-κB can induce the expression of several pro-inflammatory genes, including those encoding pro-inflammatory cytokines and chemokines, and is involved in the activation and differentiation of innate immune cells and inflammatory T cells [122]. Furthermore, triterpenoid inhibition of RANKL-induced osteoclastogenesis strongly contributes to the prevention of bone damage and disease progression in animal models of RA [87,114]. 2023, 13, x FOR PEER REVIEW 36 of 42 inflammatory cytokines and chemokines, and is involved in the activation and differentiation of innate immune cells and inflammatory T cells [122].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Triterpenes as Potential Drug Candidates for Rheumatoid Arthritis Treatment

Faustino

Pinheiro

Duarte

2023

Life

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Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation, swelling and pain. Although RA mainly affects the joints, the disease can also have systemic implications. The presence of autoantibodies, such as anti-cyclic citrullinated peptide antibodies and rheumatoid factors, is a hallmark of the disease. RA is a significant cause of disability worldwide associated with advancing age, genetic predisposition, infectious agents, obesity and smoking, among other risk factors. Currently, RA treatment depends on anti-inflammatory and disease-modifying anti-rheumatic drugs intended to reduce joint inflammation and chronic pain, preventing or slowing down joint damage and disease progression. However, these drugs are associated with severe side effects upon long-term use, including immunosuppression and development of opportunistic infections. Natural products, namely triterpenes with anti-inflammatory properties, have shown relevant anti-arthritic activity in several animal models of RA without undesirable side effects. Therefore, this review covers the recent studies (2017–2022) on triterpenes as safe and promising drug candidates for the treatment of RA. These bioactive compounds were able to produce a reduction in several RA activity indices and immunological markers. Celastrol, betulinic acid, nimbolide and some ginsenosides stand out as the most relevant drug candidates for RA treatment.

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“…The MDA-MB-231, RAW264.7 (ATCC TIB-71) murine macrophages, and C2C12 (ATCC CRL-1772) murine myoblast cell lines were cultured in DMEM (BioWest, #L0103-500) supplemented with 10% FBS and 1% penicillin/streptomycin. Bone marrow-derived macrophages (BMMs) were isolated from the tibias and femurs of 6-week-old male ICR mice (DBL Co. Ltd.), as previously described ( 24 ). The protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Kangwon National University (IACUC approval no.…”

Section: Methodsmentioning

confidence: 99%

RAS‑stimulated release of exosomal miR‑494‑3p promotes the osteolytic bone metastasis of breast cancer cells

et al. 2023

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RAS activation is a key determinant of breast cancer progression and metastasis. However, the role of the interaction among exosomes, RAS and microRNAs (miRNAs/miRs) in the osteolytic bone metastasis of breast cancer remains unclear. Therefore, the present study aimed to examine the role of activated RAS (KRAS, HRAS and NRAS) in the release of exosome-mediated osteoclastogenic miRNAs and to elucidate their functional role in bone microenvironment remodeling in vitro and in vivo . Exosomes derived from RAS-activated breast cancer cells promoted RANKL-induced osteoclastogenesis; however, RAS inhibition abolished this effect. miR-494-3p, miR-4508 and miR-6869-5p were identified as osteoclastogenic miRNAs in the exosomes secreted by RAS-activated breast cancer cells. The levels of these osteoclastogenic miRNAs in the sera of patients with human epidermal growth factor receptor 2-positive luminal breast cancer were significantly higher than those in the sera of patients with triple-negative breast cancer. miR-494-3p exhibited both osteoclastogenic and anti-osteoblastogenic activity. Treatment with a miR-494-3p inhibitor abolished the exosome-mediated increase in RANKL-induced osteoclastogenesis. Treatment with a miR-494-3p mimic enhanced RANKL-induced osteoclast formation; however, treatment with its inhibitor suppressed this effect by targeting leucine-rich repeat-containing G-protein coupled receptor 4 in osteoclast precursors. Furthermore, miR-494-3p inhibited bone morphogenetic protein 2-induced osteoblast formation by targeting semaphorin 3A. In a mouse model, exosomes derived from breast cancer cells promoted osteolytic bone lesions; however, treatment with a miR-494-3p inhibitor significantly suppressed this effect. On the whole, the present study provides a novel mechanism, demonstrating that the RAS activation of breast cancer cells induces osteolytic bone metastasis by stimulating the exosome-mediated transfer of osteoclastogenic miRNAs, including miR-494-3p to bone cells.

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Mussaendoside O, a N-triterpene cycloartane saponin, attenuates RANKL-induced osteoclastogenesis and inhibits lipopolysaccharide-induced bone loss

Cited by 15 publications

References 28 publications

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Triterpenes as Potential Drug Candidates for Rheumatoid Arthritis Treatment

RAS‑stimulated release of exosomal miR‑494‑3p promotes the osteolytic bone metastasis of breast cancer cells

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