INTRODUCTION
Although smoking and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. Mast cells (MCs) are hematopoietic cells that complete their differentiation and maturation in tissues. Excessive activation of TT+ MCs is thought to play beneficial roles in bacterial infections and preventing life-threatening internal blood clots, but adverse roles in many of inflammatory diseases. N6-methyladenosine (m6A) is mammalian cells' most prevalent internal mRNA modification. m6A participates in nearly every aspect of mRNA function and metabolism and in diverse cellular, developmental, and disease processes.In this study, we described a detailed mechanism by which MCs and their TT performed mediators play a central role in CS-induced disc degeneration.
METHODS
The discectomy outcomes were evaluated for smokers, former smokers and never smokers with12 months follow up. Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the pathological features of intervertebral disc degeneration was assessed. The role and physiology of mast cell (MC)-restricted tetramer tryptases (TT) and m6A were explored in nucleus pulpusus (NP) cells in vivo. and in vitro.
RESULTS
Patients who smoke showed poor Oswestry Disability Index (ODI) benefit compared with those who never smoked when discectomy was conducted. Mechanically, we found that smoking exposure results in the release of MC-restricted TT inside the intervertebral disc (IVD)s. Furthermore, we found that hTT can regulate the expression of methyltransferase 14 (METTL14) at epigenetic level by inducing N6-methyladenosine (m6A) deposition in the 3’-untranslated region (3’-UTR) of the transcript that encodes DIX Domain Containing 1 (DIXDC1). That reaction increases the mRNA stability and expression of DIXDC1. DIXDC1 functionally interacts with ‘Disrupted in Schizophrenia-1’ (DISC1) to accelerate the degeneration and senescence of nucleus pulposus (NP) cells by activating a canonical Wnt pathway.
SIGNIFICANCE
Our study demonstrates the association between CS, MC-derived TTs, and LBP. Our data raise the possibility that METTL14-medicated DIXDC1 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.