ArticleBiology direct2023
USP24-dependent stabilization of Runx2 recruits a p300/NCOA3 complex to transactivate ADAMTS genes and promote degeneration of intervertebral disc in chronic inflammation mice.
Article in Biology direct, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- EYA1 regulates CIITA phosphorylation to promote EYA1-CIITA-Runx2 complex formation and extracellular matrix integrity in osteoarthritis.Biology direct · 2026Article
- PRMT3-Mediated Arginine Methylation Stabilizes PCSK9 to Promote Aortic Valve Calcification.Circulation · 2026Article
- Ubiquitination in intervertebral disc degeneration: from mechanisms to potential therapeutic strategies.Journal of orthopaedic translation · 2026Review
- P300 in Inflammation: An Updated Perspective on Its Molecular Mechanisms and Therapeutic Potential.Inflammation · 2026Review
- Runx2 acetylation enhances pulmonary inflammation in chronic obstructive pulmonary disease through activating CDK8.Respiratory research · 2026Article
- Epigenome-wide exploratory study of blood DNA methylation and markers of physical performance indicates subtle differences across levels of cardiovascular fitness.Frontiers in physiology · 2026Article
- Deciphering the regulatory mechanism and therapeutic potential of ECM degradation in intervertebral disc degeneration via multi-omics integration.Frontiers in immunology · 2026Article
- Friedelin Ameliorates Nucleus Pulposus Inflammation by Increasing p65 Autophagic Degradation to Inhibit NF-κB Signalling Pathway.Journal of cellular and molecular medicine · 2026Article
- Vitamin D deficiency promotes intervertebral disc degeneration via p38/NCoR2-mediated extracellular matrix degradation.European journal of nutrition · 2025Article
- Review
- YTHDF2-dependent mCellular and molecular life sciences : CMLS · 2024Article
- USP24 promotes autophagy-dependent ferroptosis in hepatocellular carcinoma by reducing the K48-linked ubiquitination of Beclin1.Communications biology · 2024Article
- Ubiquitin recruiting chimera: more than just a PROTAC.Biology direct · 2024Review
- ALKBH5-mediated mCell & bioscience · 2024Article
- Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans.PloS one · 2024Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundIntervertebral disc degeneration (IDD) naturally occurs during the aging process. Its occurrence is closely related to chronic inflammation; however, the causal relationship between them is controversial. This study aimed to investigate if inflammation would promote IDD incidence and explore the underlying mechanism.
methodsA chronic inflammation mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS). Enzyme-linked immunosorbent assay was performed to determine proinflammatory cytokines in serum. Histological staining was used to evaluate the degeneration of IVDs. Immunoblots and RT-qPCR analyses were performed to measure protein and mRNA expression levels. Immunoprecipitation, mass spectrometry, and co-immunoprecipitation assays were used to determine the assembly of protein complex.
resultsWe found that an inflammatory microenvironment activated p38 kinase, which phosphorylated the Runx2 transcription factor at the Ser28 site. The phosphorylated Runx2 (pRunx2) then recruited a deubiquitinase, ubiquitin-specific peptidase 24 (USP24), which stabilized pRunx2 and protected it from ubiquitin-dependent proteasomal degradation. The stabilized pRunx2 recruited histone acetyltransferase p300 and nuclear receptor coactivator 3 (NCOA3) to assemble a complex. This NCOA3-p300-pRunx2 complex then transactivated the expression of 13 ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) genes, thereby promoting the degradation of extracellular matrix (ECM) in intervertebral discs (IVDs) and causing IDD. Administration of either a p38 inhibitor (doramapimod), a NCOA3 inhibitor (bufalin), or a p300 inhibitor (EML425) significantly decreased the expression of the 13 ADAMTS genes and slowed the degeneration of IVDs.
conclusionIn summary, our results demonstrate that USP24 protects pRunx2 from proteasomal degradation under chronic inflammation conditions, enabling pRunx2 to transactivate ADAMTS genes and degrade ECM. Our findings provide direct evidence that chronic inflammation triggers IDD and offer a therapeutic strategy for retarding IDD in patients with chronic inflammation.
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