A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts
Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial jo...
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| Format: | Article |
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MDPI AG
2021-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/10/2705 |
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| author | Tomasz Janczi Florian Meier Yuliya Fehrl Raimund W. Kinne Beate Böhm Harald Burkhardt |
| author_facet | Tomasz Janczi Florian Meier Yuliya Fehrl Raimund W. Kinne Beate Böhm Harald Burkhardt |
| author_sort | Tomasz Janczi |
| collection | DOAJ |
| description | Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca<sup>2+</sup>-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the constitutively cycling mechanosensitive transient receptor potential vanilloid 4 calcium channels. In addition, ADAM15 reinforces the Src-mediated activation of pannexin-1 channels required for the enhanced release of ATP, a mediator of purinergic inflammation, which is increasingly produced upon sirtuin-1 induction. |
| first_indexed | 2024-03-10T06:39:18Z |
| format | Article |
| id | doaj.art-32551a725539451db7555ab925605a08 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T06:39:18Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-32551a725539451db7555ab925605a082023-11-22T17:47:54ZengMDPI AGCells2073-44092021-10-011010270510.3390/cells10102705A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial FibroblastsTomasz Janczi0Florian Meier1Yuliya Fehrl2Raimund W. Kinne3Beate Böhm4Harald Burkhardt5Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDivision of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDivision of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, GermanyExperimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, GermanyDivision of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, GermanyDivision of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, GermanyMechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca<sup>2+</sup>-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the constitutively cycling mechanosensitive transient receptor potential vanilloid 4 calcium channels. In addition, ADAM15 reinforces the Src-mediated activation of pannexin-1 channels required for the enhanced release of ATP, a mediator of purinergic inflammation, which is increasingly produced upon sirtuin-1 induction.https://www.mdpi.com/2073-4409/10/10/2705mechanotransductionADAM15SIRT1long non-coding RNAHOTAIRTRPV4 |
| spellingShingle | Tomasz Janczi Florian Meier Yuliya Fehrl Raimund W. Kinne Beate Böhm Harald Burkhardt A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts Cells mechanotransduction ADAM15 SIRT1 long non-coding RNA HOTAIR TRPV4 |
| title | A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts |
| title_full | A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts |
| title_fullStr | A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts |
| title_full_unstemmed | A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts |
| title_short | A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts |
| title_sort | novel pro inflammatory mechanosensing pathway orchestrated by the disintegrin metalloproteinase adam15 in synovial fibroblasts |
| topic | mechanotransduction ADAM15 SIRT1 long non-coding RNA HOTAIR TRPV4 |
| url | https://www.mdpi.com/2073-4409/10/10/2705 |
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