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Early cathepsin K degradation of type II collagen in vitro and in vivo in articular cartilage.
Abstract: To characterize the initial events in the cleavage of type II collagen mediated by cathepsin K and demonstrate the presence of the resulting products in human and equine articular osteoarthritic cartilage. Equine type II collagen was digested with cathepsin K and the cleavage products characterized by mass spectrometry. Anti-neoepitope antibodies were raised against the most N-terminal cleavage products and used to investigate the progress of collagen cleavage, in vitro, and the presence of cathepsin K-derived products in equine and human osteoarthritic cartilage. Six cathepsin K cleavage sites distributed throughout the triple helical region were identified in equine type II collagen. Most of the cleavages occurred following a hydroxyproline residue. The most N-terminal site was within three residues of the previously identified site in bovine type II collagen. Western blotting using anti-neoepitope antibodies showed that the initial cleavages occurred at the N-terminal sites and this was followed by more extensive degradation resulting in products too small to be resolved by SDS gel electrophoresis. Immunohistochemical staining of cartilage sections from equine or human osteoarthritic joints showed staining in lesional areas which was not observed in non-arthritic sites. Cathepsin K cleaves triple helical collagen by erosion from the N-terminus and with subsequent progressive cleavages. The liberated fragments can be detected in osteoarthritic cartilage and may represent useful biomarkers for disease activity.
Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Publication Date: 2016-04-02 PubMed ID: 27049030DOI: 10.1016/j.joca.2016.03.016Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The research focuses on studying how cathepsin K, an enzyme, breaks down type II collagen found in cartilage, and on determining the presence of these degradation products in osteoarthritic cartilage in humans and horses. The discovery could aid in the development of biomarkers for arthritic disease monitoring.
Methodology
- Type II collagen from horse cartilage was exposed to cathepsin K, and the resulting breakdown products were analyzed via mass spectrometry – a tool to identify and quantify molecules in a sample.
- The scientists then developed specific anti-neoepitope antibodies that would attach to the cleavage products. They used these to monitor the degradation process of collagen in lab settings.
- They also investigated the presence of cathepsin K-derived breakdown products in arthritic cartilage collected from horses and humans.
Findings
- Through mass spectrometry, the researchers identified six distinct cleavage sites on the type II collagen where cathepsin K action was evident.
- Most of these cleavages took place following a structure called a hydroxyproline residue – an amino acid modified post-protein production, and common in collagen.
- Through the use of anti-neoepitope antibodies, it was revealed that the initial collagen degradation happened at these N-terminal sites. This was followed by further breakdown resulting in molecules too small to detect via SDS gel electrophoresis, a common method used to separate proteins according to their size.
Implications
- Immunohistochemical staining, a technique to visually detect specific components in tissues, showed that the breakdown products were notably present in sections of cartilage affected by arthritis. These were absent in areas not impacted by the disease.
- The fact that cathepsin K initiates the breakdown of collagen at specific sites, leading ultimately to smaller molecular fragments, underlines its role in gradual collagen degradation.
- The collagen fragments generated due to cathepsin K can be located in osteoarthritic cartilage, suggesting potential use as biomarkers to assess the activity level of the disease.
Cite This Article
APA
Mort JS, Beaudry F, Théroux K, Emmott AA, Richard H, Fisher WD, Lee ER, Poole AR, Laverty S.
(2016).
Early cathepsin K degradation of type II collagen in vitro and in vivo in articular cartilage.
Osteoarthritis Cartilage, 24(8), 1461-1469.
https://doi.org/10.1016/j.joca.2016.03.016 Publication
Researcher Affiliations
- Genetics Unit, Shriners Hospitals for Children, Montreal, Québec, Canada; Department of Surgery, McGill University, Montreal, Québec, Canada. Electronic address: jmort@shriners.mcgill.ca.
- Groupe de Recherche en Pharmacologie Animal du Québec (GREPAQ), Département de Biomédecine Vétérinaire, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
- Comparative Orthopaedic Research Laboratory, Département de Sciences Cliniques, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
- Genetics Unit, Shriners Hospitals for Children, Montreal, Québec, Canada.
- Comparative Orthopaedic Research Laboratory, Département de Sciences Cliniques, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
- Department of Surgery, McGill University, Montreal, Québec, Canada.
- Genetics Unit, Shriners Hospitals for Children, Montreal, Québec, Canada; Department of Surgery, McGill University, Montreal, Québec, Canada.
- Department of Surgery, McGill University, Montreal, Québec, Canada.
- Comparative Orthopaedic Research Laboratory, Département de Sciences Cliniques, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
MeSH Terms
- Animals
- Cartilage, Articular
- Cathepsin K
- Cattle
- Collagen Type II
- Collagenases
- Horses
- Humans
Citations
This article has been cited 12 times.- Treviño EA, Shah J, Pearson JJ, Platt MO, Xia Y, Temenoff JS. Microfluidic Platform for Microparticle Fabrication and Release of a Cathepsin Inhibitor. Tissue Eng Part C Methods 2023 Aug;29(8):361-370.
- Zou N, Liu R, Li C. Cathepsin K(+) Non-Osteoclast Cells in the Skeletal System: Function, Models, Identity, and Therapeutic Implications. Front Cell Dev Biol 2022;10:818462.
- Rousseau JC, Chapurlat R, Garnero P. Soluble biological markers in osteoarthritis. Ther Adv Musculoskelet Dis 2021;13:1759720X211040300.
- Latourte A, Kloppenburg M, Richette P. Emerging pharmaceutical therapies for osteoarthritis. Nat Rev Rheumatol 2020 Dec;16(12):673-688.
- Westermann LM, Fleischhauer L, Vogel J, Jenei-Lanzl Z, Ludwig NF, Schau L, Morellini F, Baranowsky A, Yorgan TA, Di Lorenzo G, Schweizer M, de Souza Pinheiro B, Guarany NR, Sperb-Ludwig F, Visioli F, Oliveira Silva T, Soul J, Hendrickx G, Wiegert JS, Schwartz IVD, Clausen-Schaumann H, Zaucke F, Schinke T, Pohl S, Danyukova T. Imbalanced cellular metabolism compromises cartilage homeostasis and joint function in a mouse model of mucolipidosis type III gamma. Dis Model Mech 2020 Nov 18;13(11).
- Dai R, Wu Z, Chu HY, Lu J, Lyu A, Liu J, Zhang G. Cathepsin K: The Action in and Beyond Bone. Front Cell Dev Biol 2020;8:433.
- Vidak E, Javoršek U, Vizovišek M, Turk B. Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment. Cells 2019 Mar 20;8(3).
- Löfvall H, Katri A, Dąbrowska A, Karsdal MA, Luo Y, He Y, Manon-Jensen T, Dziegiel MH, Bay-Jensen AC, Thudium CS, Henriksen K. GPDPLQ(1237)-A Type II Collagen Neo-Epitope Biomarker of Osteoclast- and Inflammation-Derived Cartilage Degradation in vitro. Sci Rep 2019 Feb 28;9(1):3050.
- Ma B, Wesolowski G, Luo B, Lifsted T, Wessner K, Adamson G, Glantschnig H, Lubbers LS. Suppression of cathepsin K biomarker in synovial fluid as a free-drug-driven process. J Circ Biomark 2019 Jan-Dec;8:1849454418821819.
- Akuri MC, Barbalho SM, Val RM, Guiguer EL. Reflections about Osteoarthritis and Curcuma longa. Pharmacogn Rev 2017 Jan-Jun;11(21):8-12.
- Brizuela L, Buchet R, Bougault C, Mebarek S. Cathepsin K Inhibitors as Potential Drugs for the Treatment of Osteoarthritis. Int J Mol Sci 2025 Mar 22;26(7).
- Ahmad SS, Ahmed F, Ahmad S, Khan MA. Proteases and Osteoporosis: A Comprehensive Review of Their Role in Bone Health. Curr Drug Targets 2025;26(7):489-505.
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