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Arthritis research & therapy2021; 23(1); 218; doi: 10.1186/s13075-021-02588-7

Hyaluronic acid synthesis, degradation, and crosslinking in equine osteoarthritis: TNF-α-TSG-6-mediated HC-HA formation.

Abstract: TNF-α-stimulated gene 6 (TSG-6) protein, a TNF-α-responsive hyaladherin, possesses enzymatic activity that can catalyze covalent crosslinks of the polysaccharide hyaluronic acid (HA) to another protein to form heavy chain-hyaluronic acid (HC-HA) complexes in pathological conditions such as osteoarthritis (OA). Here, we examined HA synthase and inflammatory gene expression; synovial fluid HA, TNF-α, and viscosity; and TSG-6-mediated HC-HA complex formation in an equine OA model. The objectives of this study were to (1) evaluate the TNF-α-TSG-6-HC-HA signaling pathway across multiple joint tissues, including synovial membrane, cartilage, and synovial fluid, and (2) determine the impact of OA on synovial fluid composition and biophysical properties. HA and inflammatory cytokine concentrations (TNF-α, IL-1β, CCL2, 3, 5, and 11) were analyzed in synovial fluid from 63 OA and 25 control joints, and HA synthase (HAS1-3), TSG-6, and hyaluronan-degrading enzyme (HYAL2, HEXA) gene expression was measured in synovial membrane and cartilage. HA molecular weight (MW) distributions were determined using agarose gel electrophoresis and solid-state nanopore measurements, and HC-HA complex formation was detected via immunoblotting and immunofluorescence. SEC-MALS was used to evaluate TSG-6-mediated HA crosslinking, and synovial fluid and HA solution viscosities were analyzed using multiple particle-tracking microrheology and microfluidic measurements, respectively. TNF-α concentrations were greater in OA synovial fluid, and TSG6 expression was upregulated in OA synovial membrane and cartilage. TSG-6-mediated HC-HA complex formation was greater in OA synovial fluid and tissues than controls, and HC-HA was localized to both synovial membrane and superficial zone chondrocytes in OA joints. SEC-MALS demonstrated macromolecular aggregation of low MW HA in the presence of TSG-6 and inter-α-inhibitor with concurrent increases in viscosity. Synovial fluid TNF-α concentrations, synovial membrane and cartilage TSG6 gene expression, and HC-HA complex formation were increased in equine OA. Despite the ability of TSG-6 to induce macromolecular aggregation of low MW HA with resultant increases in the viscosity of low MW HA solutions in vitro, HA concentration was the primary determinant of synovial fluid viscosity rather than HA MW or HC-HA crosslinking. The TNF-α-TSG-6-HC-HA pathway may represent a potential therapeutic target in OA.
© 2021. The Author(s).
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Publication Date: 2021-08-20 PubMed ID: 34416923PubMed Central: PMC8377964DOI: 10.1186/s13075-021-02588-7Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • U.S. Gov't
  • Non-P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article focuses on understanding the role of a particular protein — TNF-α-stimulated gene 6 (TSG-6) — and its impact on hyaluronic acid in the context of equine osteoarthritis. It explores the relationship between inflammation and the behavior of hyaluronic acid and the potential therapeutic implications in treating osteoarthritis.

About the Research

  • The article investigates the synthesis, degradation, and crosslinking of hyaluronic acid (HA) in relation to equine osteoarthritis, a joint disorder in horses caused by inflammation.
  • The study focuses on the TNF-α-stimulated gene 6 (TSG-6) protein and its potential enzymatic activities, particularly its ability to bond HA to another protein thereby forming HC-HA complexes.

Objectives of the Study

  • The research aimed to evaluate the TNF-α-TSG-6-HC-HA signaling pathway across multiple joint tissues (synovial membrane, cartilage, synovial fluid), which are known to be affected by osteoarthritis.
  • It also sought to identify the impact of osteoarthritis on the composition and physical properties of synovial fluid, which is a substance that lubricates and provides nutrients to the cartilage in joints.

Methods and Analysis

  • Analysis of HA and inflammatory cytokine concentrations was carried out in synovial fluid from a total of 63 osteoarthritic and 25 control joints.
  • The HA synthase (HAS1-3), TSG-6, and hyaluronan-degrading enzyme gene expression was measured in synovial membrane and cartilage.
  • Various scientific methods and measures were employed in the study, such as agarose gel electrophoresis, solid-state nanopore measurements, immunoblotting, and immunofluorescence.

Findings and Conclusions

  • The studies found that TNF-α concentrations were greater in synovial fluid from osteoarthritic joints, and TSG6 expression was upregulated in osteoarthritic synovial membrane and cartilage.
  • Despite TSG-6’s ability to induce macromolecular aggregation of HA with resultant increases in the viscosity of low MW HA solutions in vitro, the HA concentration was primarily responsible for determining synovial fluid viscosity.
  • The research concludes that the TNF-α-TSG-6-HC-HA pathway might be a potential therapeutic target for treating osteoarthritis, offering an encouraging direction for future studies and treatments.

Cite This Article

APA
Fasanello DC, Su J, Deng S, Yin R, Colville MJ, Berenson JM, Kelly CM, Freer H, Rollins A, Wagner B, Rivas F, Hall AR, Rahbar E, DeAngelis PL, Paszek MJ, Reesink HL. (2021). Hyaluronic acid synthesis, degradation, and crosslinking in equine osteoarthritis: TNF-α-TSG-6-mediated HC-HA formation. Arthritis Res Ther, 23(1), 218. https://doi.org/10.1186/s13075-021-02588-7

Publication

Arthritis research & therapy
ISSN: 1478-6362
NlmUniqueID: 101154438
Country: England
Language: English
Volume: 23
Issue: 1
Pages: 218
PII: 218

Researcher Affiliations

Fasanello, Diana C
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Su, Jin
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Deng, Siyu
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Yin, Rose
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
  • Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA.
Colville, Marshall J
  • Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA.
Berenson, Joshua M
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Kelly, Carolyn M
  • Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Freer, Heather
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Rollins, Alicia
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Wagner, Bettina
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Rivas, Felipe
  • Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Hall, Adam R
  • Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Rahbar, Elaheh
  • Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
DeAngelis, Paul L
  • Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Paszek, Matthew J
  • Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA.
Reesink, Heidi L
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. hlr42@cornell.edu.

MeSH Terms

  • Animals
  • Chondrocytes
  • Horses
  • Hyaluronic Acid
  • Osteoarthritis / genetics
  • Synovial Fluid
  • Tumor Necrosis Factor-alpha

Grant Funding

  • 2015-67015-23072 / National Institute of Food and Agriculture
  • P01 HL107147 / NHLBI NIH HHS
  • R24 GM08291 / NIH HHS
  • R01 GM134226 / NIH HHS
  • R01 GM134226 / NIGMS NIH HHS
  • UL1 TR001420 / NCATS NIH HHS
  • 2019-67015-29833 / National Institute of Food and Agriculture
  • K08 AR068469 / NIAMS NIH HHS
  • K08AR068469 / NIAMS NIH HHS

Conflict of Interest Statement

Adam R. Hall, Elaheh Rahbar, and Paul L. DeAngelis are included as inventors on a patent describing SS-nanopore technology.

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