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Papers of the Week

Papers: 17 Jun 2023 - 23 Jun 2023

Basic Science

Animal Studies, Molecular/Cellular, Neurobiology

Inflammation/Inflammatory, Musculoskeletal Pain

2023 Jun 19

Mol Ther


Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 modification.


Tu J, Li W, Hansbro PM, Yan Q, Bai X, Donovan C, Kim RY, Galvao I, Das A, Yang C, Zou J, Diwan A


Although cigarette smoke (CS) and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. We had 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 also show that MCs and their proteases induce degenerative musculoskeletal disease. By using mice custom-designed smoke-exposure system, we demonstrated that CS results in intervertebral disc (IVDs) degeneration and the release of MC-restricted tetramer tryptases (TT) inside the IVDs. TT was found to regulate the expression of methyltransferase 14 (METTL14) at the 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. Our study demonstrates the association between CS, MC-derived TTs, and LBP. These findings 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.