Liposomal α-cyperone targeting bone resorption surfaces suppresses osteoclast differentiation and osteoporosis progression via the PI3K/Akt axis

Osteoporosis is a metabolic dysregulation of bone that occurs mainly in postmenopausal women, and the hyperfunction of osteoclasts is the primary contributor to postmenopausal osteoporosis. However, the development of effective therapeutic drugs and precise delivery systems remains a challenge in the field of anti-absorption therapy. Here, we reported the alpha-cyperone (alpha-CYP) for anti-osteoporosis and developed a liposome-based nano-drug delivery system of alpha-CYP, that specifically targets the bone resorption interface. Firstly, we found that the alpha-CYP, one of the major sesquiterpenes of Cyperus rotundus L., attenuated the progression of osteoporosis in ovariectomized (OVX) mice and down-regulated the expression of phosphorylated proteins of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), causing down-regulation of osteoclast-related genes/proteins and curbing osteoclast differentiation. Furthermore, alpha-CYP reversed the activation of osteoclastic differentiation and enhanced osteoporosis-related proteins expression caused by PI3K/Akt agonist (YS-49). More importantly, we adopted the osteoclastic resorption surface targeting peptide Asp8 and constructed the liposome (lipaC@Asp8) to deliver alpha-CYP to osteoclasts and confirmed its anti-osteoporosis effect and enhanced osteoclast inhibition by blocking PI3K/Akt axis. In conclusion, this study demonstrated that alpha-CYP inhibits osteoclast differentiation and osteoporosis development by silencing PI3K/Akt pathway, and the liposome targeting delivery systems loaded with alpha-CYP might provide a novel and effective strategy to treat osteoporosis.

Automated summary

This study investigates the potential of alpha-cyperone (alpha-CYP) as a therapeutic agent for osteoporosis and develops a liposome-based nano-drug delivery system that specifically targets bone resorption. The results demonstrate that alpha-CYP inhibits osteoclast differentiation and the progression of osteoporosis by silencing the PI3K/Akt pathway. The liposome targeting delivery system loaded with alpha-CYP shows enhanced efficacy in inhibiting osteoclasts and may provide a novel strategy for treating osteoporosis.