dc.contributor.author | Thompson, C | en_US |
dc.contributor.author | Knight, M | en_US |
dc.contributor.author | Gupta, H | en_US |
dc.contributor.author | Wang, W | en_US |
dc.contributor.author | INAMDAR, S | en_US |
dc.contributor.author | Das, B | en_US |
dc.contributor.author | Fu, S | en_US |
dc.contributor.author | Meng, H | en_US |
dc.contributor.editor | Block, JA | en_US |
dc.date.accessioned | 2020-08-28T10:50:52Z | |
dc.date.available | 2020-08-12 | en_US |
dc.identifier.issn | 1063-4584 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/66682 | |
dc.description.abstract | Objective: Cartilage health is maintained in response to a range of mechanical stimuli including compressive, shear and tensile strains and associated alterations in osmolality. The osmotic-sensitive ion channel Transient Receptor Potential Vanilloid 4 (TRPV4) is required for mechanotransduction. Mechanical stimuli inhibit interleukin-1β (IL-1β) mediated inflammatory signalling, however the mechanism is unclear. This study aims to clarify the role of TRPV4 in this response. Design: TRPV4 activity was modulated (GSK205 antagonist or GSK1016790A (GSK101) agonist) in articular chondrocytes and cartilage explants in the presence or absence of IL-1β, mechanical (10% cyclic tensile strain (CTS), 0.33Hz, 24hrs) or osmotic loading (200mOsm, 24hrs). Nitric oxide (NO), prostaglandin E2 (PGE2) and sulphated glycosaminoglycan (sGAG) release and cartilage biomechanics were analysed. Alterations in post-translational tubulin modifications and primary cilia length regulation were examined. Results: In isolated chondrocytes, mechanical loading inhibited IL-1β mediated NO and PGE2 release. This response was inhibited by GSK205. Similarly, osmotic loading was anti-inflammatory in cells and explants, this response was abrogated by TRPV4 inhibition. In explants, GSK101 inhibited IL-1β mediated NO release and prevented cartilage degradation and loss of mechanical properties. Upon activation, TRPV4 cilia localisation was increased resulting in HDAC6-dependent modulation of soluble tubulin and altered cilia length regulation. Conclusion: Mechanical, osmotic or pharmaceutical activation of TRPV4 regulates HDAC6-dependent modulation of ciliary tubulin and is anti-inflammatory. This study reveals for the first time, the potential of TRPV4 manipulation as a novel therapeutic mechanism to supress pro-inflammatory signalling and cartilage degradation. | en_US |
dc.publisher | Elsevier | en_US |
dc.relation.ispartof | Osteoarthritis and Cartilage | en_US |
dc.rights | This is a pre-copyedited, author-produced version of an article accepted for publication in Osteoarthritis and Cartilage following peer review. | |
dc.subject | cartilage | en_US |
dc.subject | cilia | en_US |
dc.subject | hypo-osmolarity | en_US |
dc.subject | mechanobiology | en_US |
dc.subject | mechanotransduction, | en_US |
dc.subject | TRPV4 | en_US |
dc.subject | IL-1β | en_US |
dc.title | Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction | en_US |
dc.type | Article | |
dc.rights.holder | © 2020 Elsevier B.V. | |
pubs.notes | Not known | en_US |
pubs.publication-status | Accepted | en_US |
dcterms.dateAccepted | 2020-08-12 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |
qmul.funder | The mechanics of the collagen fibrillar network in ageing cartilage::Biotechnology and Biological Sciences Research Council | en_US |