Spine Labs, St. George & Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, NSW, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.
Mol Ther. 2023 Aug 2;31(8):2524-2542. doi: 10.1016/j.ymthe.2023.06.010. Epub 2023 Jun 19.
Although cigarette smoking (CS) and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. We have shown that excessive activation of mast cells (MCs) and their proteases play key roles in CS-associated diseases, like asthma, chronic obstructive pulmonary disease (COPD), blood coagulation, and lung cancer. Previous studies have also shown that MCs and their proteases induce degenerative musculoskeletal disease. By using a custom-designed smoke-exposure mouse system, we demonstrated that CS results in intervertebral disc (IVD) degeneration and release of MC-restricted tetramer tryptases (TTs) in the IVDs. TTs were found to regulate the expression of methyltransferase 14 (METTL14) at the epigenetic level by inducing N6-methyladenosine (mA) deposition in the 3' untranslated region (UTR) of the transcript that encodes dishevelled-axin (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. Our study demonstrates the association between CS, MC-derived TTs, and LBP. These findings raise the possibility that METTL14-medicated DIXDC1 mA modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.
虽然吸烟（CS）和腰痛（LBP）在全球范围内很常见，但它们之间的相关性及其作用机制尚不清楚。我们已经表明，肥大细胞（MCs）及其蛋白酶的过度激活在 CS 相关疾病中发挥关键作用，如哮喘、慢性阻塞性肺疾病（COPD）、血液凝固和肺癌。先前的研究还表明，MCs 和它们的蛋白酶会引起退行性肌肉骨骼疾病。通过使用定制的烟雾暴露小鼠系统，我们证明 CS 会导致椎间盘（IVD）退化，并在 IVD 中释放 MC 限制的四聚体胰蛋白酶（TTs）。研究发现，TTs 通过在编码盘状结构域包含蛋白 1（DIXDC1）的转录物的 3'非翻译区（UTR）中诱导 N6-甲基腺苷（mA）沉积，在表观遗传水平上调节甲基转移酶 14（METTL14）的表达。该反应增加了 Dixdc1 的 mRNA 稳定性和表达。DIXDC1 与精神分裂症 1 （DISC1）功能相互作用，通过激活经典 Wnt 途径加速核髓核（NP）细胞的退化和衰老。我们的研究证明了 CS、MC 衍生的 TT 与 LBP 之间的关联。这些发现提出了这样一种可能性，即 METTL14 介导的 DIXDC1 mA 修饰可能成为阻止 LBP 患者 NP 退化发展的潜在治疗靶点。
