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

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Abstract

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 α-cyperone (α-CYP) for anti-osteoporosis and developed a liposome-based nano-drug delivery system of α-CYP, that specifically targets the bone resorption interface. Firstly, we found that the α-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, α-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 α-CYP to osteoclasts and confirmed its anti-osteoporosis effect and enhanced osteoclast inhibition by blocking PI3K/Akt axis. In conclusion, this study demonstrated that α-CYP inhibits osteoclast differentiation and osteoporosis development by silencing PI3K/Akt pathway, and the liposome targeting delivery systems loaded with α-CYP might provide a novel and effective strategy to treat osteoporosis.

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Acknowledgements

This work was supported by the National Key Research and Development Project (No. 2021YFA1201404), Major Project of the National Natural Science Foundation of China (Nos. 81991514, 82272530), Jiangsu Province Medical Innovation Center of Orthopedic Surgery (No. CXZX202214), Jiangsu Provincial Key Medical Center Foundation, Jiangsu Provincial Medical Outstanding Talent Foundation, Jiangsu Provincial Medical Youth Talent Foundation, Jiangsu Provincial Key Medical Talent Foundation, and the Fundamental Research Funds for the Central Universities (Nos. 14380493 and 14380494).

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  1. Lin Yang and Xueying An contributed equally to this work.

Authors and Affiliations

  1. Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing, 210008, China

    Lin Yang & Qing Jiang

  2. Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Nanjing, 210008, China

    Lin Yang, Xueying An, Wang Gong, Wenshu Wu, Bin Liu, Rui Peng & Qing Jiang

  3. State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University & Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China

    Xueying An, Wang Gong, Wenshu Wu, Bin Liu, Xiaoyan Shao, Yansi Xian, Rui Peng, Baosheng Guo & Qing Jiang

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  1. Lin Yang
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  2. Xueying An
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Correspondence to Baosheng Guo or Qing Jiang.

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Yang, L., An, X., Gong, W. et al. Liposomal α-cyperone targeting bone resorption surfaces suppresses osteoclast differentiation and osteoporosis progression via the PI3K/Akt axis. Nano Res. 17, 2949–2959 (2024). https://doi.org/10.1007/s12274-023-6224-7

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