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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.
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