ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP PRSYM
    • 2016-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • Register
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 1063

Role of Mitochondrial-Bound HK2 in Rheumatoid Arthritis Fibroblast-like Synoviocytes

Patricia Oliveira1, Marta Fernandez Bustmanate2, Ricard Garcia Carbonell3, Elsa Sanchez-Lopez4, Teresina Laragione5, Percio S. Gulko6, Gary S. Firestein7, Anne N Murphy3, Shigeki Miyamoto8 and Monica Guma7,9, 1Medicine, UCSD, San Diego, CA, 2Medicine, UCSD, La Jolla, CA, 3Pharmacology, UCSD, San Diego, CA, 4Department of Pharmacology, School of Medicine. UCSD., La Jolla, CA, 5Medicine/Rheumatology, Icahn School of Medicine at Mount Sinai, New York, NY, 6Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 7Medicine, University of California San Diego, La Jolla, CA, 8Pharmacology, UCSD, La Jolla, CA, 9Medicine, Autonomous University of Barcelona, Bellatera, Spain

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, mitochondria and rheumatoid arthritis (RA)

  • Tweet
  • Email
  • Print
Save to PDF
Session Information

Date: Monday, October 22, 2018

Session Title: Rheumatoid Arthritis – Etiology and Pathogenesis Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Hexokinases (HKs) catalyze the first step in glucose metabolism. HK2 constitutes the principal inducible isoform with a restricted distribution in normal adult tissues. Fibroblast-like synoviocytes (FLS) are a key component of rheumatoid arthritis (RA) invasive synovium, and display unique aggressive features, including increased migration and invasion. We have recently showed a critical role of glucose metabolism and specifically of HK2 in RA FLS phenotype. Of interest, HK2 localizes not only in the cytosol but also at mitochondria and protects mitochondria against apoptosis. We hypothesize that mitochondrial-bound HK2 is key regulator of RA FLS phenotype.

Methods: HK2 localization at baseline and after RA FLS activation with platelet derived growth factor (PDGF, 10ng/ml) was evaluated by cell fractionation and western blot (WB), and confocal microscopy. RA FLS were infected with GFP, full-length (FL)-HK2 or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (ad). RA FLS were also incubated with metiljasmonate (MJ, 2.5mM), which dissociates HK2 from mitochondria. FLS function in medium and PDGF stimulated cells was evaluated by measuring 1) migration of cultured FLS monolayers (scratch assay); 2) in vitro invasion assay using matrigel. For arthritis experiments, mice were injected with K/BxN sera on day 0. MJ (25mg/kg) was injected daily i.p. beginning on day 0 after serum administration or starting at the peak of arthritis (from day 5). Clinical arthritis scores were serially assessed. Joint histology was evaluated using a semiquantitative scoring system.

Results: 30 minutes after PDGF stimulation, cell fractionation and confocal microscopy revealed that PDGF induced the translocation of HK2 to the mitochondrial fraction. Overexpression of the HK2 mutant reversed the invasive phenotype induced by full-length HK2 after PDGF stimualtion, and also FLS migration rate, GFP-ad: 101.2 ±12.69; FL-HK2-ad: 135.7±38.88; HK2ΔN-ad 112.6±35.72 (FL-HK2-ad vs. HK2ΔN-ad: p<0.01). MJ treatment also significantly reduced RA FLS invasion from 46.79±8,961 to 22.45±7.48 (p<0.001) and migration rate from 253±14 to 152±6 (p<0.001) after PDGF stimulation. Finally, MJ treatment significantly decreased arthritis severity. Day 10 scores were 4.8±0.9 and 1.2±0.58 (P<0.01) for vehicle and MJ-treated mice respectively, when mice were treated from day 0 after serum administration, and 12.5±0.5 and 9.2±0.663 (p<0.05) for vehicle and MJ-treated mice when mice were treated from day 5. Joint histology scores for vehicle and MJ-treated mice from day 0 were: for inflammation 0.9±0.821 and 0.4±0.42 (p<0.05), bone erosion scores were 1.5±0.61 and 0.3±0.45 (p<0.01), and cartilage damage scores were 1.9±0.42 and 0.3±0.45 (p<0.01), respectively.

Conclusion: Our results suggest that mitochondrial HK2 is key regulator of aggressive FLS phenotype, which contributes to joint destruction in RA. Targeting HK2, as an isoform-specific contributor to RA FLS phenotype, offers a safer approach than global glycolysis inhibition. Other possible strategy to improve selectivity would be to target HK2 binding to the mitochondria.


Disclosure: P. Oliveira, None; M. Fernandez Bustmanate, None; R. Garcia Carbonell, None; E. Sanchez-Lopez, None; T. Laragione, None; P. S. Gulko, None; G. S. Firestein, None; A. N. Murphy, None; S. Miyamoto, None; M. Guma, None.

To cite this abstract in AMA style:

Oliveira P, Fernandez Bustmanate M, Garcia Carbonell R, Sanchez-Lopez E, Laragione T, Gulko PS, Firestein GS, Murphy AN, Miyamoto S, Guma M. Role of Mitochondrial-Bound HK2 in Rheumatoid Arthritis Fibroblast-like Synoviocytes [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/role-of-mitochondrial-bound-hk2-in-rheumatoid-arthritis-fibroblast-like-synoviocytes/. Accessed January 22, 2021.
  • Tweet
  • Email
  • Print
Save to PDF

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-mitochondrial-bound-hk2-in-rheumatoid-arthritis-fibroblast-like-synoviocytes/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Convergence: Where Rheumatology Meets. All Virtual. November 5-9.

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2021 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies
loading Cancel
Post was not sent - check your email addresses!
Email check failed, please try again
Sorry, your blog cannot share posts by email.
This site uses cookies: Find out more.