Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 m6 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

Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 m6 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

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Mol Ther, 2023, 31, (8), pp. 2524-2542
Issue Date:: 2023-08-02

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Field	Value	Language
dc.contributor.author	Tu, J
dc.contributor.author	Li, W
dc.contributor.author	Hansbro, PM
dc.contributor.author	Yan, Q
dc.contributor.author	Bai, X
dc.contributor.author	Donovan, C https://orcid.org/0000-0003-4558-329X
dc.contributor.author	Kim, RY
dc.contributor.author	Galvao, I
dc.contributor.author	Das, A
dc.contributor.author	Yang, C
dc.contributor.author	Zou, J
dc.contributor.author	Diwan, A
dc.date.accessioned	2023-08-09T05:14:32Z
dc.date.available	2023-06-14
dc.date.available	2023-08-09T05:14:32Z
dc.date.issued	2023-08-02
dc.identifier.citation	Mol Ther, 2023, 31, (8), pp. 2524-2542
dc.identifier.issn	1525-0016
dc.identifier.issn	1525-0024
dc.identifier.uri	http://hdl.handle.net/10453/171760
dc.description.abstract	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 (m6A) 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 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1023131
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1175134
dc.relation.ispartof	Mol Ther
dc.relation.isbasedon	10.1016/j.ymthe.2023.06.010
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	06 Biological Sciences, 10 Technology, 11 Medical and Health Sciences
dc.subject.classification	Biotechnology
dc.subject.classification	3105 Genetics
dc.subject.classification	3202 Clinical sciences
dc.subject.classification	3206 Medical biotechnology
dc.title	Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 m6 modification.
dc.type	Journal Article
utslib.citation.volume	31
utslib.location.activity	United States
utslib.for	06 Biological Sciences
utslib.for	10 Technology
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	closed_access	*
dc.date.updated	2023-08-09T05:14:30Z
pubs.issue	8
pubs.publication-status	Published
pubs.volume	31
utslib.citation.issue	8

Abstract:

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 (m6A) 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 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.

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http://hdl.handle.net/10453/171760