Abstract
Osteoporosis, which typically affects postmenopausal women, is an osteolytic disease due to over-activation of osteoclasts. However, current drugs targeting osteoclast inhibition face various side effects, making natural compounds with great interest as alternative treatment options. Cycloastragenol (CAG) is a triterpenoid with multiple biological activities. Previously, CAG’s activity against aging-related osteoporosis was reported, but the mechanisms of actions for the activities were not understood. This study demonstrated that CAG dose-dependently inhibited osteoclast formation in receptor activator of nuclear factor-κB ligand (RANKL)-stimulated bone marrow macrophage (BMMs). Mechanism studies showed that CAG inhibited NF-κB, calcium, and nuclear factor of activated T cells 1 (NFATc1) pathways. Additionally, CAG also promoted the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/anti-oxidative response element (ARE) pathway that scavenges reactive oxygen species (ROS). Furthermore, CAG was also found to prevent bone loss of postmenopausal osteoporosis (PMO) in a preclinical model of ovariectomized (OVX) mice. Collectively, our research confirms that CAG inhibits the formation and function of osteoclasts by regulating RANKL-induced intracellular signaling pathways, which may represent a promising alternative for the therapy of osteoclast-related disease.
Highlights
Osteoporosis is a systemic disease designated by lowered bone mass and microstructure damage, usually resulting in an increased risk of fractures (No-Authors-Listed, 1993)
Calcium regulates the expression of c-Fos, a significant component of activator protein-1 (AP-1), through a non-calcineurin dependent pathway, which promotes the initial induction and auto-amplification of nuclear factor of activated T cells 1 (NFATc1) and the expression of osteoclast-specific genes like Acid phosphatase 5 (Acp5), Matrix metalloprotein 9 (Mmp9) (Sundaram et al, 2007), vacuolar H+ transporting ATPase V0 subunit D2 (Atp6v0d2) (Feng et al, 2009), Cathepsin K (Ctsk) (Pang et al, 2019)
The count of multinucleated cells (MNCs) with more than three nuclei stained positively for tartrateresistant acid phosphatase (TRAcP) revealed that the increase of CAG doses was correlated with the depletion in the number of RANKL-induced osteoclasts (Figures 1C,D)
Summary
Osteoporosis is a systemic disease designated by lowered bone mass and microstructure damage, usually resulting in an increased risk of fractures (No-Authors-Listed, 1993). Mainstream drugs that target inhibiting fracture risks in patients with PMO (Black et al, 1996), their side effects cast uncertainty on the use of these drugs and reduce public acceptance (Jha et al, 2015; Black et al, 2020). Due to their safety and effectiveness on bone-related disease, natural. The inhibitory effect of NRF2 on ROS production negatively regulates RANKL-induced formation and activity of osteoclast (Hyeon et al, 2013) These pieces of evidence suggest that the study of RANKL-induced pathways is essential for screening antiosteoclast drugs
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