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Identification of Proteinase Activated Receptor (PAR) cleaving enzymes in human osteoarthritis knee joint synovial fluids

Arundhasa Chandrabalan, View ORCID ProfileAndrew Firth, View ORCID ProfileRobert B Litchfield, C Thomas Appleton, View ORCID ProfileAlan Getgood, View ORCID ProfileRithwik Ramachandran
doi: https://doi.org/10.1101/2020.10.21.336693
Arundhasa Chandrabalan
aDepartment of Physiology and Pharmacology, Bone and Joint Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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Andrew Firth
bDivision of Orthopedic Surgery, Bone and Joint Institute, Fowler Kennedy Sport Medicine Clinic, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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Robert B Litchfield
bDivision of Orthopedic Surgery, Bone and Joint Institute, Fowler Kennedy Sport Medicine Clinic, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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C Thomas Appleton
aDepartment of Physiology and Pharmacology, Bone and Joint Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
cDepartment of Medicine, Bone and Joint Institute, The Dr. Sandy Kirkley Centre for Musculoskeletal Research, Schulich School of Medicine and Dentistry, London, Ontario, Canada
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Alan Getgood
bDivision of Orthopedic Surgery, Bone and Joint Institute, Fowler Kennedy Sport Medicine Clinic, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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Rithwik Ramachandran
aDepartment of Physiology and Pharmacology, Bone and Joint Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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  • For correspondence: rramach@uwo.ca
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ABSTRACT

Objective Osteoarthritis (OA) is the most prevalent joint disorder with incidence increasing worldwide. Mechanistic insights into OA pathophysiology are still evolving and there are currently no disease-modifying OA drugs available. It is well established that an increase in proteolytic enzyme activity is linked to progressive degradation of the cartilage in OA. Proteolytic enzymes can also trigger inflammation through activation of a family of G-protein coupled receptors (GPCRs) called the Proteinase Activated Receptors (PARs). Here we sought to characterize the PAR activating enzyme repertoire in human OA knee joint fluids.

Methods Human knee joint synovial fluids derived from twenty-five OA patients and four healthy donors were screened for PAR cleavage activity using novel genetically encoded human PAR biosensor expressing cells. The class or type of enzymes cleaving the PARs was further characterized using enzyme-selective inhibitors and enzyme-specific fluorogenic substrates.

Results Activity of PAR1, PAR2 and PAR4 activating enzymes were identified at substantially different levels in OA patients relative to healthy knee joint synovial fluids. Using enzyme class or type selective inhibitors and fluorogenic substrates we found that serine proteinases, including thrombin-like enzymes, trypsin-like enzymes, and matrix metalloproteinases are the major PAR activating enzymes present in the OA knee synovial fluids.

Conclusions Multiple enzymes activating PAR1, PAR2 and PAR4 are present in OA joint fluids. PAR signalling can trigger pro-inflammatory responses and targeting PARs has been proposed as a therapeutic approach in OA. Knowledge of the PAR activators present in the human knee joint will guide study of relevant signaling events and enable future development of novel PAR targeted therapies for OA and other inflammatory joint diseases.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 22, 2020.
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Identification of Proteinase Activated Receptor (PAR) cleaving enzymes in human osteoarthritis knee joint synovial fluids
Arundhasa Chandrabalan, Andrew Firth, Robert B Litchfield, C Thomas Appleton, Alan Getgood, Rithwik Ramachandran
bioRxiv 2020.10.21.336693; doi: https://doi.org/10.1101/2020.10.21.336693
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Identification of Proteinase Activated Receptor (PAR) cleaving enzymes in human osteoarthritis knee joint synovial fluids
Arundhasa Chandrabalan, Andrew Firth, Robert B Litchfield, C Thomas Appleton, Alan Getgood, Rithwik Ramachandran
bioRxiv 2020.10.21.336693; doi: https://doi.org/10.1101/2020.10.21.336693

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