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CARMA3 Drives NF-κB Activation and Promotes Intervertebral Disc Degeneration: Involvement of CARMA3-BCL10-MALT1 Signalosome

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Abstract

Intervertebral disc degeneration (IDD) diseases are common and frequent diseases in orthopedics. The caspase recruitment domain (CARD) and membrane-associated guanylate kinase-like protein 3 (CARMA3) is crucial in the activation of the NF-κB pathway. However, the biological function of CARMA3 in IDD remains unknown. Here, CARMA3 expression was elevated in nucleus pulposus (NP) tissues of IDD rats and nutrient deprivation (ND)-induced NP cells. The main pathological manifestations observed in IDD rats were shrinkage of the NP, reduction of NP cells, fibrosis of NP tissues, and massive reduction of proteoglycans. These changes were accompanied by a decrease in the expression of collagen II and aggrecan, an increase in the expression of the extracellular matrix (ECM) catabolic proteases MMP-3, MMP-13, and metalloprotease with ADAMTS-5, and an increase in the activity of the pro-apoptotic protease caspase-3. The expression of p-IκBαSer32/36 and p-p65Ser536 was also upregulated. However, these effects were reversed with the knockdown of CARMA3. Mechanistically, CARMA3 bound to BCL10 and MALT1 to form a signalosome. Knockdown of CARMA3 reduced the CARMA3-BCL10-MALT1 signalosome-mediated NF-κB activation. CARMA3 activated the NF-κB signaling pathway in a manner that bound to BCL10 and MALT1 to form a signalosome, which affects NP cell damage and is involved in the development of IDD. This supports CARMA3-BCL10-MALT1-NF-κB as a promising targeting axis for the treatment of IDD.

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Data Availability

Data in this study are available from the corresponding author upon reasonable request.

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  1. Department of Orthopedics, Central Hospital of Dalian University of Technology, No. 826 Xinan Road, Dalian, People’s Republic of China

    Yadong Liu, Guiqi Zhang, Jiani Wu, Yi Meng, Jianyu Hu, Hao Fu & Dongfang Yang

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Contributions

YDL and DFY were responsible for the conceptualization and design of this study. YDL, GQZ, JNW, YM, JYH, and HF conducted the experiments and collected the data. YDL, GQZ, and JNW analyzed and interpreted the data. YDL drafted the manuscript. DFY supervised and managed the study. All authors approved the final Manuscript.

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Correspondence to Dongfang Yang.

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Liu, Y., Zhang, G., Wu, J. et al. CARMA3 Drives NF-κB Activation and Promotes Intervertebral Disc Degeneration: Involvement of CARMA3-BCL10-MALT1 Signalosome. Inflammation (2024). https://doi.org/10.1007/s10753-024-02016-3

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