{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:09:28Z","timestamp":1785521368777,"version":"3.56.0"},"reference-count":65,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T00:00:00Z","timestamp":1633737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG BU 584\/6-1"],"award-info":[{"award-number":["DFG BU 584\/6-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dr. Robert-Pfleger Stiftung","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 Ca2+-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.<\/jats:p>","DOI":"10.3390\/cells10102705","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T21:19:32Z","timestamp":1633900772000},"page":"2705","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts"],"prefix":"10.3390","volume":"10","author":[{"given":"Tomasz","family":"Janczi","sequence":"first","affiliation":[{"name":"Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Meier","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliya","family":"Fehrl","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6104-482X","authenticated-orcid":false,"given":"Raimund W.","family":"Kinne","sequence":"additional","affiliation":[{"name":"Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-3131","authenticated-orcid":false,"given":"Harald","family":"Burkhardt","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60590 Frankfurt am Main, Germany"},{"name":"Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.immuni.2017.02.006","article-title":"Immunopathogenesis of rheumatoid arthritis","volume":"46","author":"Firestein","year":"2017","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/s41584-020-0413-5","article-title":"Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes","volume":"16","author":"Nygaard","year":"2020","journal-title":"Nat. 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