SwePub
Sök i LIBRIS databas

  Extended search

onr:"swepub:oai:gup.ub.gu.se/325919"
 

Search: onr:"swepub:oai:gup.ub.gu.se/325919" > Amplification of In...

  • 1 of 1
  • Previous record
  • Next record
  •    To hitlist
  • Elsaid, K. (author)

Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023-03-10
  • Wiley,2023

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/325919
  • https://gup.ub.gu.se/publication/325919URI
  • https://doi.org/10.1002/art.42413DOI

Supplementary language notes

  • Language:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Objective In gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin-1 beta (IL-1 beta)-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)/EULAR gout classification criteria (the proband).Methods We conducted whole-genome sequencing, quantitative proteomics, whole-blood RNA-sequencing analysis using serum samples from the proband. We used a mouse model of IL-1 beta-induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout.Results Lubricin level was attenuated in human proband serum and associated with elevated acute-phase reactants and inflammatory whole-blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of inter-alpha trypsin inhibitor heavy chain 3, an inhibitor of lubricin-degrading cathepsin G. Changes in the proband's serum protein interactome network supported enhanced lubricin degradation, with cathepsin G activity increased relative to its inhibitors, SERPINB6 and thrombospondin 1. Activation of Toll-like receptor 2 (TLR-2) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (P < 0.01). Lubricin blunted urate crystal precipitation and IL-1 beta induction of xanthine oxidase and urate in cultured macrophages (P < 0.001). In lubricin-deficient mice, injection of IL-1 beta in knees increased xanthine oxidase-positive synovial resident M1 macrophages (P < 0.05).Conclusion Our findings linked normouricemic erosive gout to attenuated lubricin, with impaired control of cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization and blunted IL-1 beta-induced increases in xanthine oxidase and urate in macrophages. The collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated cathepsin G, and synovial fibroblast TLR-2 signaling.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Merriman, T. R. (author)
  • Rossitto, L. A. (author)
  • Liu-Bryan, R. (author)
  • Karsh, J. (author)
  • Phipps-Green, A. (author)
  • Jay, G. D. (author)
  • Elsayed, S. (author)
  • Qadri, M. (author)
  • Miner, M. (author)
  • Cadzow, M. (author)
  • Dambruoso, T. J. (author)
  • Schmidt, T. A. (author)
  • Dalbeth, N. (author)
  • Chhana, A. (author)
  • Höglund, Jennifer,1993Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine (author)
  • Ghassemian, M. (author)
  • Campeau, A. (author)
  • Maltez, N. (author)
  • Karlsson, Niclas G.,1966Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology(Swepub:gu)xkanic (author)
  • Gonzalez, D. J. (author)
  • Terkeltaub, R. (author)
  • Göteborgs universitetInstitutionen för biomedicin (creator_code:org_t)

Related titles

  • In:Arthritis & Rheumatology: Wiley75:5, s. 794-8052326-51912326-5205

Internet link

Find in a library

To the university's database

  • 1 of 1
  • Previous record
  • Next record
  •    To hitlist

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Close

Copy and save the link in order to return to this view