Targeting chaperone-mediated autophagy to regulate osteoclast activity as a therapeutic strategy for osteoporosis

Yunhui Zhang; Quanfeng Li; Xiaoshuai Peng; Pengfei Ji; Yibin Zhang; Jiahao Jin; Zihao Yuan; Jianan Jiang; Guangqi Tian; Mingxi Cai; Pei Feng; Yanfeng Wu; Wenjie Liu; Peng Wang

doi:10.1016/j.mtbio.2025.102311

Targeting chaperone-mediated autophagy to regulate osteoclast activity as a therapeutic strategy for osteoporosis

Mater Today Bio. 2025 Sep 17:35:102311. doi: 10.1016/j.mtbio.2025.102311. eCollection 2025 Dec.

Authors

Yunhui Zhang^{1

2}, Quanfeng Li^{1

2}, Xiaoshuai Peng^{1

2}, Pengfei Ji^{1

2}, Yibin Zhang^{1

2}, Jiahao Jin^{1

2}, Zihao Yuan^{1

2}, Jianan Jiang^{1

2}, Guangqi Tian^{1

2}, Mingxi Cai^{1

2}, Pei Feng^{2

3}, Yanfeng Wu^{2

3}, Wenjie Liu^{1

2}, Peng Wang^{1

2}

Affiliations

¹ Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China.
² Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518033, PR China.
³ Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China.

Abstract

Osteoporosis is an age-related bone metabolic disease characterized by a persistent bone mass decrease and bone structure destruction. Osteoclasts, important cells in the bone remodelling process, are closely associated with the onset and progression of osteoporosis; however, the regulatory mechanisms involved remain unclear. In this study, TFE3 cytoplasmic translocation inhibited LAMP2A expression in osteoclasts and precursors in elderly individuals with osteoporosis and the downregulation of LAMP2A expression mediated the attenuation of chaperone-mediated autophagy (CMA). This inhibition prevented intracellular CCR5 degradation, increased the osteoclast differentiation of osteoclast precursor cells, and enhanced the bone resorption activity of mature osteoclasts, leading to bone loss and remodelling. In addition, we constructed osteoclast-targeted nanoparticles carrying CMA activators and demonstrated that enhancing osteoclast CMA activity in vivo inhibited the abnormal bone resorption activity of osteoclasts, thereby effectively increasing bone mass and alleviating osteoporosis progression. This study revealed that LAMP2A-mediated CMA activity in osteoclasts and their precursors negatively regulates osteoclast differentiation and bone resorption activities both in vivo and in vitro. The attenuation of LAMP2A-mediated CMA activity plays an important role in the development of osteoporosis, and enhancing LAMP2A-mediated CMA activity represents a potential therapeutic strategy for osteoporosis.

Keywords: Chaperone-mediated autophagy; Osteoclast; Osteoporosis; Targeted delivery system.