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The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence

Fan Zhang1,2,3, Yuan Wang1,2, Luyang Zhang1,2

  • 1Xuanwu Hospital Capital Medical University, Beijing, China.

Elife
|July 7, 2025
PubMed

Insights

CHMP5 protein dysfunction disrupts the endolysosomal pathway, leading to skeletal cell senescence and bone abnormalities. Eliminating senescent cells offers a potential therapy for these musculoskeletal disorders.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Skeletal Biology

Background:

  • Endolysosomal pathway dysfunction, observed in lysosomal storage diseases, is linked to musculoskeletal disorders.
  • The precise mechanisms connecting endolysosomal dysfunction to skeletal abnormalities are not well understood, hindering therapeutic development.

Purpose of the Study:

  • To investigate the role of CHMP5 in maintaining the endolysosomal pathway and regulating bone formation.
  • To elucidate the molecular mechanisms by which endolysosomal dysfunction leads to musculoskeletal abnormalities.

Main Methods:

  • Genetic ablation of CHMP5 in mouse osteogenic cells.
  • In vivo and in vitro bone formation assays.
  • Analysis of endolysosomal and mitochondrial function, reactive oxygen species (ROS) levels, and cell senescence.
  • Evaluation of senolytic drug efficacy in CHMP5 knockout mice.

Main Results:

  • Genetic deletion of CHMP5 in osteogenic cells enhanced bone formation.
  • CHMP5 deficiency led to endolysosomal dysfunction, decreased VPS4A protein, impaired mitochondrial function, and increased mitochondrial ROS.
  • These cellular changes resulted in skeletal cell senescence, causing abnormal bone formation.
  • Elimination of senescent cells using senolytic drugs ameliorated musculoskeletal abnormalities in CHMP5 knockout mice.

Conclusions:

  • CHMP5 is crucial for endolysosomal pathway integrity and normal bone development.
  • Endolysosomal dysfunction, mediated by CHMP5 loss, drives skeletal cell senescence via mitochondrial impairment.
  • Cellular senescence is a key mechanism underlying musculoskeletal disorders associated with endolysosomal pathway defects and presents a therapeutic target.
Keywords:
CHMP5bonecell biologycell senescenceendolysosomal pathwaymedicinemousemusculoskeletal diseaseskeletal stem cell

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