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Safranal inhibits estrogen-deficiency osteoporosis by targeting Sirt1 to interfere with NF-κB acetylation
Sun-Ren Sheng1, Yu-Hao Wu1, Zi-Han Dai1
1Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109# Xueyuan Road, Wenzhou 325000, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, 270# Xueyuan Road, Wenzhou 325000, Zhejiang Province, China.
Background:
Osteoporosis is a prevalent bone metabolic disease in menopause, and long-term medication is accompanied by serious side effects. Estrogen deficiency-mediated hyperactivated osteoclasts is the initiating factor for bone loss, which is regulated by nuclear factor-κB (NF-κB) signaling. Safranal (Saf) is a monoterpene aldehyde produced from Saffron (Crocus sativus L.) and possesses multiple biological properties, particularly the anti-inflammatory property. However, Saf's role in osteoporosis remains unknown.
Purpose:
This study aims to validate the role of Saf in osteoporosis and explore the potential mechanism.
Study Design:
The RANKL-exposed mouse BMM (bone marrow monocytes) and the castration-mediated osteoporosis model were applied to explore the effect and mechanism of Saf in vitro and in vivo.
Method:
The effect of Saf on osteoclast formation and function were assessed by TRAcP staining, bone-resorptive experiment, qPCR, immunoblotting and immunofluorescence, etc. Micro-CT, HE, TRAcP and immunohistochemical staining were performed to estimate the effects of Saf administration on OVX-mediated osteoporosis in mice at imaging and histological levels.
Results:
Saf concentration-dependently inhibited RANKL-mediated osteoclast differentiation without affecting cellular viability. Meanwhile, Saf-mediated anti-osteolytic capacity and Sirt1 upregulation were also found in ovariectomized mice. Mechanistically, Saf interfered with NF-κB signaling by activating Sirt1 to increase p65 deacetylation and inactivating IKK to decrease IκBα degradation.
Conclusion:
Our results support the potential application of Saf as a therapeutic agent for osteoporosis.
Insights
Safranal (Saf) inhibits osteoclast formation, a key factor in osteoporosis. This natural compound may offer a new therapeutic approach for bone loss by modulating nuclear factor-κB (NF-κB) signaling.
Area of Science:
- Biochemistry
- Pharmacology
- Bone Biology
Background:
- Osteoporosis is a common postmenopausal bone disease driven by estrogen deficiency and hyperactive osteoclasts.
- Nuclear factor-κB (NF-κB) signaling pathways regulate osteoclast activity and bone loss.
- Safranal (Saf), derived from Saffron, has anti-inflammatory properties, but its effect on osteoporosis is unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of Safranal (Saf) in osteoporosis.
- To elucidate the underlying molecular mechanisms of Saf's action on bone metabolism.
Main Methods:
- In vitro studies using RANKL-stimulated mouse bone marrow monocytes (BMM).
- In vivo studies utilizing an ovariectomized (OVX) mouse model of osteoporosis.
- Assessment of osteoclast differentiation, function, and bone resorption markers.
- Analysis of NF-κB signaling pathway components and Sirtuin 1 (Sirt1) activity.
Main Results:
- Safranal inhibited RANKL-induced osteoclast differentiation concentration-dependently without impacting cell viability.
- In OVX mice, Saf demonstrated anti-osteolytic effects and upregulated Sirt1 expression.
- Saf modulated NF-κB signaling by activating Sirt1, leading to p65 deacetylation and IKK inactivation, thus reducing IκBα degradation.
Conclusions:
- Safranal exhibits therapeutic potential for treating osteoporosis.
- Saf's mechanism involves the Sirt1-mediated inhibition of the NF-κB pathway, crucial for controlling osteoclast activity.
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