Mast cells and smoking interaction in intervertebral disc degeneration — The International Society for the Study of the Lumbar Spine
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Mast cells and smoking interaction in intervertebral disc degeneration (3173)

Ashish Diwan 1 , Ji Tu 1 , Philip Hansbro 2 3 , Abhirup Das 1 , Cao Yang 4 , Jun Zou 5
  1. The University of New South Wales, Sydney, NSW, Australia
  2. Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, NSW, Australia
  3. Centre for Inflammation, Centenary Institute, and University of Technology Sydney, Sydeny, NSW, Australia
  4. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HUBEI, China
  5. The First Affiliated Hospital of Soochow University, Soochow, China

Introduction: Both smoking and low back pain (LBP) are common conditions worldwide. However, the correlations and molecular mechanisms between them are lacking.

Methods: Prospective observational study was conducted to evaluate the clinical outcomes in 56 discectomy patients who are smokers, former smokers, and never smokers. Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, development of spinal pain and intervertebral disc degeneration (IVDD) were assessed by micro-CT, differentiation assay, proteomics analysis, and histology. These models showed hallmark features of mast cell (MC) activation. The functions of human bone marrow-derived MCs from LBP patients who are smokers and never smokers were analyzed in vitro. The role of MCs tryptase in IVDD pathogenesis were evaluated by in vivo and in vitro studies. MCs tryptase potential targeting for nucleus pulposus cells was examined using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq). The MCs tryptase regulated RNA stability and binding target gene were assessed by RNA stability assay and RNA immunoprecipitation assays. The MCs tryptase targeted protein-protein interaction were explored by co-immunoprecipitation and proteomics.

Results: Current smoking status showed poor back pain VAS and ODI scores compared with never smokers. The in vivo study showed smoking exposure can induce disc degeneration in mouse models. Smoking exposure can induce mast cells activation and tryptase release inside the disc tissues. Tryptase-beta promotes nucleus pulposus (NP) degeneration via N6-Methyladenosine (m6A)-mediated upregulation of DIX Domain Containing 1 (DIXDC1) which is m6A “writer” protein, METTL14, regulated. The upregulated DIXDC1 were revealed to impact NP cells senescence and cell cycle.

Discussion: This study provided clues that smoking can induce disc degeneration as a single factor. It also revealed the detailed molecular mechanisms of how smoking exposure has effect on human NP cells. This study provided therapeutic targets for low back pain patients, especially those smokers.  

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