The marine drug plitidepsin alleviates osteoporosis in estrogen-deficient mice by suppressing ROS-mediated NRF2/HO-1 signaling and osteoclast formation

Abstract

Marine-derived compounds represent an important source of innovative therapeutics owing to their structural diversity and broad bioactivity; however, their potential in osteoporosis therapy remains insufficiently explored. This study investigated the effects of plitidepsin (Pli), a marine-origin cyclic peptide, on osteoclast differentiation and bone loss associated with estrogen deficiency. Osteoclastogenesis was induced in mouse bone marrow–derived macrophages using receptor activator of nuclear factor-κ B ligand (RANKL) and macrophage-stimulating factor (M-CSF). The impact of Pli on osteoclast formation, resorptive function, and intracellular reactive oxygen species (ROS) was evaluated. Osteoclast-related gene expression was quantified by qPCR, while key signaling pathways involved in oxidative stress and differentiation were examined by Western blotting. An ovariectomized (OVX) mouse model was employed to assess the in vivo effects of Pli on bone mass and microarchitecture. Pli suppressed osteoclast formation and function in vitro, as evidenced by reduced multinucleated cell formation, disrupted actin ring assembly, decreased bone resorption, and downregulated osteoclast-specific genes. In OVX mice, Pli alleviated trabecular bone loss and preserved bone microstructural integrity. Mechanistically, Pli attenuated ROS accumulation and enhanced antioxidant defense through activation of the NRF2/HO-1 pathway. Plitidepsin effectively mitigates estrogen deficiency–induced bone loss by inhibiting osteoclast differentiation and activity, highlighting its therapeutic potential for osteoporosis.