2. Academic Validation
  3. Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

  • Exp Mol Med. 2022 Sep;54(9):1549-1562. doi: 10.1038/s12276-022-00849-2.
Chunlei Liu  # 1 2 3,  Peng Li  # 1,  Xiang Ao  # 1,  Zhengnan Lian 3,  Jie Liu 3,  Chenglong Li 1,  Minjun Huang 3,  Liang Wang 4,  Zhongmin Zhang 5 6
Affiliations

Affiliations

  • 1 Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangdong Province, Guangzhou, China.
  • 2 Division of Spine Surgery, Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangdong Province, Qingyuan, China.
  • 3 Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangdong Province, Guangzhou, China.
  • 4 Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangdong Province, Guangzhou, China. liang091@aliyun.com.
  • 5 Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangdong Province, Guangzhou, China. nfzzm@163.com.
  • 6 Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangdong Province, Guangzhou, China. nfzzm@163.com.
  • # Contributed equally.
PMID: 36131026 DOI: 10.1038/s12276-022-00849-2
Abstract

Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal canal stenosis (LSCS). The pathomechanisms for LFH have not been fully elucidated. Isobaric tags for relative and absolute quantitation (iTRAQ) technology, proteomics assessments of human ligamentum flavum (LF), and successive assays were performed to explore the effect of clusterin (CLU) upregulation on LFH pathogenesis. LFH samples exhibited higher cell positive rates of the CLU, TGF-β1, α-SMA, ALK5 and p-SMAD3 proteins than non-LFH samples. Mechanical stress and TGF-β1 initiated CLU expression in LF cells. Notably, CLU inhibited the expression of mechanical stress-stimulated and TGF-β1-stimulated COL1A2 and α-SMA. Mechanistic studies showed that CLU inhibited mechanical stress-stimulated and TGF-β1-induced SMAD3 activities through suppression of the phosphorylation of SMAD3 and by inhibiting its nuclear translocation by competitively binding to ALK5. PRKD3 stabilized CLU protein by inhibiting lysosomal distribution and degradation of CLU. CLU attenuated mechanical stress-induced LFH in vivo. In summary, the findings showed that CLU attenuates mechanical stress-induced LFH by modulating the TGF-β1 pathways in vitro and in vivo. These findings imply that CLU is induced by mechanical stress and TGF-β1 and inhibits LF fibrotic responses via negative feedback regulation of the TGF-β1 pathway. These findings indicate that CLU is a potential treatment target for LFH.

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