2. Academic Validation
  3. PP2Ac Regulates Autophagy via Mediating mTORC1 and ULK1 During Osteoclastogenesis in the Subchondral Bone of Osteoarthritis

PP2Ac Regulates Autophagy via Mediating mTORC1 and ULK1 During Osteoclastogenesis in the Subchondral Bone of Osteoarthritis

  • Adv Sci (Weinh). 2024 Jul 23:e2404080. doi: 10.1002/advs.202404080.
Haifeng Zhang 1 2,  Gaoran Ge 1,  Wei Zhang 1,  Houyi Sun 3,  Xiaolong Liang 1,  Yu Xia 1,  Jiacheng Du 4,  Zerui Wu 1 5,  Jiaxiang Bai 1 6,  Huilin Yang 1,  Xing Yang 7,  Jun Zhou 1,  Yaozeng Xu 1,  Dechun Geng 1
Affiliations

Affiliations

  • 1 Department of Orthopedics Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China.
  • 2 Department of Orthopaedic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 3 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, 250063, China.
  • 4 Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Jeonbuk, 54896, South Korea.
  • 5 Department of Orthopedics, Changshu Hospital Affiliated to Soochow University, Changshu, Jiangsu, 215501, China.
  • 6 Department of Orthopedics, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 234000, China.
  • 7 Orthopedics and Sports Medicine Center, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, 242, Guangji Road, Suzhou, Jiangsu, 215008, China.
PMID: 39041921 DOI: 10.1002/advs.202404080
Abstract

The molecular mechanism underlying abnormal osteoclastogenesis triggering subchondral bone remodeling in osteoarthritis (OA) is still unclear. Here, single-cell and bulk transcriptomics Sequencing analyses are performed on GEO datasets to identify key molecules and validate them using knee joint tissues from OA patients and rat OA models. It is found that the catalytic subunit of protein Phosphatase 2A (PP2Ac) is highly expressed during osteoclastogenesis in the early stage of OA and is correlated with Autophagy. Knockdown or inhibition of PP2Ac weakened Autophagy during osteoclastogenesis. Furthermore, the ULK1 expression of the downstream genes is significantly increased when PP2Ac is knocked down. PP2Ac-mediated Autophagy is dependent on ULK1 phosphorylation activity during osteoclastogenesis, which is associated with enhanced dephosphorylation of ULK1 Ser637 residue regulating at the post-translational level. Additionally, mTORC1 inhibition facilitated the expression level of PP2Ac during osteoclastogenesis. In animal OA models, decreasing the expression of PP2Ac ameliorated early OA progression. The findings suggest that PP2Ac is also a promising therapeutic target in early OA.

Keywords

PP2Ac; ULK1; autophagy; dephosphorylation; mTORC1; osteoclastogenesis.

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