2. Academic Validation
  3. The V-ATPase a3 subunit deficiency affects osteoarthritis via mTOR-Mediated autophagy levels in subchondral bone

The V-ATPase a3 subunit deficiency affects osteoarthritis via mTOR-Mediated autophagy levels in subchondral bone

  • Biochem Pharmacol. 2025 Jul 18:241:117180. doi: 10.1016/j.bcp.2025.117180.
Jianxin Qiu 1,  Xiaohang Zheng 2,  Jiajing Ye 1,  Tao Yang 3,  Xiaotong Wei 1,  Ting Jiang 3,  Yuhang Gong 1,  Zhenghua Hong 4,  Haixiao Chen 5,  Jie Xiang 6
Affiliations

Affiliations

  • 1 Orthopedic Department, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China; Enze Medical Research Center, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China.
  • 2 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
  • 3 Enze Medical Research Center, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China.
  • 4 Orthopedic Department, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China; Enze Medical Research Center, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China. Electronic address: 0001hzh@163.com.
  • 5 Orthopedic Department, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China; Enze Medical Research Center, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China. Electronic address: chenhx@tzhospital.com.
  • 6 Orthopedic Department, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China; Enze Medical Research Center, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, China. Electronic address: xiangj@enzemed.com.
PMID: 40684994 DOI: 10.1016/j.bcp.2025.117180
Abstract

Autophagy is an evolutionarily conserved cellular self-degradation process that eliminates damaged organelles and misfolded proteins, thereby maintaining cellular homeostasis and delaying Apoptosis and tissue degeneration. The efficient progression of Autophagy depends on the maintenance of intracellular homeostasis, in which vacuolar ATPases (V-ATPases) play a crucial role by facilitating lysosomal acidification. Among these, the a3 subunit of V-ATPase, encoded by the T-cell immune regulator 1 (TCIRG1, also known as ATP6V0a3), is highly expressed in osteoclasts. However, its regulatory function in osteoarthritis (OA) remains largely unexplored. Our study found a reduction in TCIRG1 expression in the subchondral bone of OA patients and DMM (destabilization of the medial meniscus) mice. Additionally, TCIRG1 heterozygous knockout (HET) mice exhibited an abnormally thickened subchondral bone phenotype and impaired bone resorption. TCIRG1 is critical for lysosomal acidification and facilitates the completion of Autophagy by promoting the fusion of late phagosomes with lysosomes. We further used rapamycin to restore partial Autophagy and found that the treatment restored osteoclast resorption and also protected the articular cartilage matrix. Our findings demonstrate that TCIRG1 contributes to OA progression through regulation of autophagic activity. The results offer novel mechanistic insights into OA pathogenesis and support the potential of TCIRG1 as both a therapeutic target and a diagnostic biomarker.

Keywords

Autophagosome-lysosome fusion; Autophagy; Bone resorption; Osteoarthritis; TCIRG1; mTOR.

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