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Updated: Aug 21, 2025

Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy
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Rapamycin regulates osteogenic differentiation through Parkin-mediated mitophagy in rheumatoid arthritis

Qiyue Chen1, Kai Fan1, Guangbao Song1

  • 1Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China.

International Immunopharmacology
|November 15, 2022
PubMed

Insights

Rheumatoid arthritis (RA) causes bone loss. Targeting the mTORC1 pathway and mitophagy with rapamycin and TNF-α blockers may treat RA-associated osteoporosis by improving mitochondrial function.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Immunology

Background:

  • Rheumatoid arthritis (RA) is characterized by bone destruction and loss, but the mechanisms of associated osteoporosis are not fully understood.
  • Mitophagy, a process regulating mitochondrial quality, is implicated in preosteoblast differentiation and function.
  • The role of Parkin, a protein involved in mitophagy and inflammation, in RA-related osteoporosis remains unclear.

Purpose of the Study:

  • To investigate the role of the mechanistic target of rapamycin (mTORC1) pathway and mitophagy in rheumatoid arthritis (RA)-associated bone metabolism.
  • To explore the potential of targeting Parkin-mediated mitophagy and the mTORC1 pathway for treating osteoporosis in RA.

Main Methods:

  • Examined the effects of tumor necrosis factor alpha (TNF-α) on preosteoblasts, assessing Parkin expression, mitophagy, and mitochondrial damage.
  • Utilized rapamycin (RAPA), an mTORC1 inhibitor, to evaluate its impact on mitophagy and mitochondrial function in TNF-α-stimulated preosteoblasts.
  • Assessed the therapeutic efficacy of combined TNF-α neutralization and RAPA in an in vivo mouse model of arthritis-induced osteoporosis (AIA).

Main Results:

  • Abnormal bone metabolism in RA was linked to mTORC1 pathway activation and chronic inflammation affecting preosteoblast differentiation via mitophagy.
  • TNF-α stimulation led to increased Parkin expression and mitochondrial damage in preosteoblasts.
  • Rapamycin treatment enhanced Parkin-mediated mitophagy, mitigating mitochondrial impairment induced by TNF-α.
  • Combination therapy with a TNF-α neutralizing antibody and RAPA significantly reduced osteoporosis in AIA mice.

Conclusions:

  • The mTORC1 pathway and mitophagy are critical in regulating bone metabolism during RA.
  • Parkin-mediated mitophagy plays a protective role against TNF-α-induced mitochondrial damage in preosteoblasts.
  • Combined inhibition of TNF-α and the mTORC1 pathway represents a promising therapeutic strategy for managing osteoporosis in RA patients.
Keywords:
MitophagyOsteoporosisParkinRapamycinRheumatoid arthritis

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