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

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.