Dynamics of Connexin 43 Down Modulation in Human Articular Chondrocytes Stimulated by Tumor Necrosis Factor Alpha
Connexin 43 (Cx43) exerts pivotal functions in articular chondrocytes (CH). It is involved in the communication among cells and between cells and the extracellular environment, and it contributes to the maintenance of the correct cell phenotype. The pro-inflammatory cytokine TNFα induces a reduction...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/10/5575 |
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| author | Elena Della Morte Stefania Niada Chiara Giannasi Luigi Zagra Anna Teresa Brini |
| author_facet | Elena Della Morte Stefania Niada Chiara Giannasi Luigi Zagra Anna Teresa Brini |
| author_sort | Elena Della Morte |
| collection | DOAJ |
| description | Connexin 43 (Cx43) exerts pivotal functions in articular chondrocytes (CH). It is involved in the communication among cells and between cells and the extracellular environment, and it contributes to the maintenance of the correct cell phenotype. The pro-inflammatory cytokine TNFα induces a reduction in Cx43 expression in CH. Here, we studied the dynamics of this decrease in expression. We evaluated Cx43 protein and gene expression and the involvement of C-terminal domain (CTD) cleavage and proteasomal degradation. Treatments able to counteract TNFα action were also examined, together with Gap Junction (GJ) functionality and Cx43 localization. TNFα induced a significant reduction in Cx43 expression already at day 1, and the down modulation reached a peak at day 3 (−46%). The decrease was linked to neither gene expression modulation nor CTD cleavage. Differently, the proteasome inhibitor MG132 reverted TNFα effect, indicating the involvement of proteasomal degradation in Cx43 reduction. In addition, the co-treatment with the anabolic factor TGF-β1 restored Cx43 levels. Cx43 decrease occurred both at the membrane level, where it partially influenced GJ communication, and in the nucleus. In conclusion, TNFα induced a rapid and lasting reduction in Cx43 expression mostly via the proteasome. The down modulation could be reverted by cartilage-protective factors such as MG132 and TGF-β1. These findings suggest a possible involvement of Cx43 perturbation during joint inflammation. |
| first_indexed | 2024-03-10T03:44:54Z |
| format | Article |
| id | doaj.art-e70f7d32c8b7447c864c339d09ff85d9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:44:54Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e70f7d32c8b7447c864c339d09ff85d92023-11-23T11:24:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012310557510.3390/ijms23105575Dynamics of Connexin 43 Down Modulation in Human Articular Chondrocytes Stimulated by Tumor Necrosis Factor AlphaElena Della Morte0Stefania Niada1Chiara Giannasi2Luigi Zagra3Anna Teresa Brini4IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, ItalyIRCCS Istituto Ortopedico Galeazzi, 20161 Milan, ItalyIRCCS Istituto Ortopedico Galeazzi, 20161 Milan, ItalyIRCCS Istituto Ortopedico Galeazzi, 20161 Milan, ItalyIRCCS Istituto Ortopedico Galeazzi, 20161 Milan, ItalyConnexin 43 (Cx43) exerts pivotal functions in articular chondrocytes (CH). It is involved in the communication among cells and between cells and the extracellular environment, and it contributes to the maintenance of the correct cell phenotype. The pro-inflammatory cytokine TNFα induces a reduction in Cx43 expression in CH. Here, we studied the dynamics of this decrease in expression. We evaluated Cx43 protein and gene expression and the involvement of C-terminal domain (CTD) cleavage and proteasomal degradation. Treatments able to counteract TNFα action were also examined, together with Gap Junction (GJ) functionality and Cx43 localization. TNFα induced a significant reduction in Cx43 expression already at day 1, and the down modulation reached a peak at day 3 (−46%). The decrease was linked to neither gene expression modulation nor CTD cleavage. Differently, the proteasome inhibitor MG132 reverted TNFα effect, indicating the involvement of proteasomal degradation in Cx43 reduction. In addition, the co-treatment with the anabolic factor TGF-β1 restored Cx43 levels. Cx43 decrease occurred both at the membrane level, where it partially influenced GJ communication, and in the nucleus. In conclusion, TNFα induced a rapid and lasting reduction in Cx43 expression mostly via the proteasome. The down modulation could be reverted by cartilage-protective factors such as MG132 and TGF-β1. These findings suggest a possible involvement of Cx43 perturbation during joint inflammation.https://www.mdpi.com/1422-0067/23/10/5575Connexin 43articular chondrocytesTNFαproteasomeTGF-β1 |
| spellingShingle | Elena Della Morte Stefania Niada Chiara Giannasi Luigi Zagra Anna Teresa Brini Dynamics of Connexin 43 Down Modulation in Human Articular Chondrocytes Stimulated by Tumor Necrosis Factor Alpha International Journal of Molecular Sciences Connexin 43 articular chondrocytes TNFα proteasome TGF-β1 |
| title | Dynamics of Connexin 43 Down Modulation in Human Articular Chondrocytes Stimulated by Tumor Necrosis Factor Alpha |
| title_full | Dynamics of Connexin 43 Down Modulation in Human Articular Chondrocytes Stimulated by Tumor Necrosis Factor Alpha |
| title_fullStr | Dynamics of Connexin 43 Down Modulation in Human Articular Chondrocytes Stimulated by Tumor Necrosis Factor Alpha |
| title_full_unstemmed | Dynamics of Connexin 43 Down Modulation in Human Articular Chondrocytes Stimulated by Tumor Necrosis Factor Alpha |
| title_short | Dynamics of Connexin 43 Down Modulation in Human Articular Chondrocytes Stimulated by Tumor Necrosis Factor Alpha |
| title_sort | dynamics of connexin 43 down modulation in human articular chondrocytes stimulated by tumor necrosis factor alpha |
| topic | Connexin 43 articular chondrocytes TNFα proteasome TGF-β1 |
| url | https://www.mdpi.com/1422-0067/23/10/5575 |
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