Abstract
The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.
Competing Interest Statement
The study started when the corresponding author (X. Ge) worked at the University of Massachusetts Medical School and a previous manuscript related to this study was posted on bioRxiv (https://doi.org/10.1101/2020.08.03.233874). To complete the study for a peer-reviewed publication, the co-first authors and X. Ge generated a novel Chmp5-floxed mouse strain, re-established all animal and cell models in the current laboratory in Beijing, China, and added novel critical experiments to make the conclusion convincing and the study comprehensive. Therefore, we reorganized the data and wrote it as a new paper. All authors agree on the current version of the paper, including its authorship and conclusions. J.H.S. is a scientific co-founder of AAVAA Therapeutics and holds equity in this company but does not have conflicts of interest with this study. Other authors declare no competing interests.
Footnotes
The study started when the corresponding author (X. Ge) worked at the University of Massachusetts Medical School and the previous manuscript related to this study was posted on bioRxiv in the year 2020. To complete the study for a peer-reviewed publication, the co-first authors in the current manuscript and X. Ge generated a novel Chmp5-floxed mouse strain, re-established all animal and cell models in the current laboratory in Beijing, China, and added novel critical experiments to make the conclusion convincing and the study comprehensive. Therefore, we reorganized the data and wrote it as a new paper. All authors agree on the current version of the paper, including its authorship and conclusions.
