TY  - JOUR
A1  - Janczi, Tomasz
A1  - Meier, Florian Matthias Peter
A1  - Fehrl, Yuliya
A1  - Kinne, Raimund W.
A1  - Böhm, Beate
A1  - Burkhardt, Harald
T1  - A novel pro-inflammatory mechanosensing pathway orchestrated by the disintegrin metalloproteinase ADAM15 in synovial fibroblasts
T2  - Cells
N2  - 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.
KW  - ADAM15
KW  - HOTAIR
KW  - SIRT1
KW  - TRPV4
KW  - long non-coding RNA
KW  - mechanotransduction
KW  - pannexin-1
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/81660
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-816602
SN  - 2073-4409
N1  - This research was funded by the Deutsche Forschungsgemeinschaft (DFG BU 584/6-1), the Dr. Robert-Pfleger Stiftung, and the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD).
VL  - 10
IS  - 10, art. 2705
SP  - 1
EP  - 21
PB  - MDPI
CY  - Basel
ER  -