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Cleavage of Cartilage Oligomeric Matrix Protein (COMP) by ADAMTS4 generates a neoepitope associated with osteoarthritis and other forms of degenerative joint disease

de Groot, Rens ; Folgado, Patricia Badía ; Yamamoto, Kazuhiro ; Martin, Daniel R ; Koch, Christopher D ; Debruin, Danielle ; Blagg, Sophie ; Minns, Alexander F ; Bhutada, Sumit and Ahnström, Josefin , et al. (2025) In Matrix Biology 135. p.106-124
Abstract

Osteoarthritis (OA) is a highly prevalent joint disease, affecting millions of people worldwide and characterized by degradation of articular cartilage, subchondral bone remodeling and low-grade inflammation, leading to pain, stiffness and disability. Cartilage Oligomeric Matrix Protein (COMP) is a major structural component of cartilage and its degradation has been proposed as a marker of OA severity/progression. Several proteases cleave COMP in vitro, however, it is unclear which of these COMPase activities is prevalent in an osteoarthritic joint. Here, using purified recombinant proteins, we show that A Disintegrin And Metalloproteinase with Thrombospondin motifs 4 (ADAMTS4) is the most potent COMPase, followed by ADAMTS1. Using... (More)

Osteoarthritis (OA) is a highly prevalent joint disease, affecting millions of people worldwide and characterized by degradation of articular cartilage, subchondral bone remodeling and low-grade inflammation, leading to pain, stiffness and disability. Cartilage Oligomeric Matrix Protein (COMP) is a major structural component of cartilage and its degradation has been proposed as a marker of OA severity/progression. Several proteases cleave COMP in vitro, however, it is unclear which of these COMPase activities is prevalent in an osteoarthritic joint. Here, using purified recombinant proteins, we show that A Disintegrin And Metalloproteinase with Thrombospondin motifs 4 (ADAMTS4) is the most potent COMPase, followed by ADAMTS1. Using liquid chromatography-tandem mass spectrometry, we identified several novel cleavage sites in COMP resulting from ADAMTS4 and ADAMTS1 activity. Cleavage at S 77-V 78 disrupted the pentameric organization of COMP and generated a neopeptide previously identified in the synovial fluid of OA patients. Immunoblots with anti-QQS 77 antibodies confirmed that ADAMTS4 efficiently cleaved this peptide bond. By analyzing five ADAMTS4 variants, we found that the C-terminal spacer domain is strictly necessary for COMPase activity and identified the specific residues involved in the interaction with COMP. An inhibitory anti-ADAMTS4 antibody significantly decreased generation of the COMP QQS 77 neoepitope in human OA cartilage explants, implicating ADAMTS4 as a key protease in generating the QQS 77 neopeptides in OA. Since another majorADAMTS4 substrate is aggrecan, the most abundant proteoglycan in cartilage, these findings highlight that, by cleaving both COMP and aggrecan, ADAMTS4 may play a crucial role in modulating the structural integrity of cartilage.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Matrix Biology
volume
135
pages
106 - 124
publisher
Elsevier
external identifiers
  • scopus:85212821966
  • pmid:39672391
ISSN
1569-1802
DOI
10.1016/j.matbio.2024.12.005
language
English
LU publication?
yes
additional info
Copyright © 2024. Published by Elsevier B.V.
id
e09bf86c-0bc3-4d3f-b8d5-113ed7176dcc
date added to LUP
2025-01-14 14:27:04
date last changed
2025-07-03 07:22:50
@article{e09bf86c-0bc3-4d3f-b8d5-113ed7176dcc,
  abstract     = {{<p>Osteoarthritis (OA) is a highly prevalent joint disease, affecting millions of people worldwide and characterized by degradation of articular cartilage, subchondral bone remodeling and low-grade inflammation, leading to pain, stiffness and disability. Cartilage Oligomeric Matrix Protein (COMP) is a major structural component of cartilage and its degradation has been proposed as a marker of OA severity/progression. Several proteases cleave COMP in vitro, however, it is unclear which of these COMPase activities is prevalent in an osteoarthritic joint. Here, using purified recombinant proteins, we show that A Disintegrin And Metalloproteinase with Thrombospondin motifs 4 (ADAMTS4) is the most potent COMPase, followed by ADAMTS1. Using liquid chromatography-tandem mass spectrometry, we identified several novel cleavage sites in COMP resulting from ADAMTS4 and ADAMTS1 activity. Cleavage at S 77-V 78 disrupted the pentameric organization of COMP and generated a neopeptide previously identified in the synovial fluid of OA patients. Immunoblots with anti-QQS 77 antibodies confirmed that ADAMTS4 efficiently cleaved this peptide bond. By analyzing five ADAMTS4 variants, we found that the C-terminal spacer domain is strictly necessary for COMPase activity and identified the specific residues involved in the interaction with COMP. An inhibitory anti-ADAMTS4 antibody significantly decreased generation of the COMP QQS 77 neoepitope in human OA cartilage explants, implicating ADAMTS4 as a key protease in generating the QQS 77 neopeptides in OA. Since another majorADAMTS4 substrate is aggrecan, the most abundant proteoglycan in cartilage, these findings highlight that, by cleaving both COMP and aggrecan, ADAMTS4 may play a crucial role in modulating the structural integrity of cartilage. </p>}},
  author       = {{de Groot, Rens and Folgado, Patricia Badía and Yamamoto, Kazuhiro and Martin, Daniel R and Koch, Christopher D and Debruin, Danielle and Blagg, Sophie and Minns, Alexander F and Bhutada, Sumit and Ahnström, Josefin and Larkin, Jonathan and Aspberg, Anders and Önnerfjord, Patrik and Apte, Suneel S and Santamaria, Salvatore}},
  issn         = {{1569-1802}},
  language     = {{eng}},
  pages        = {{106--124}},
  publisher    = {{Elsevier}},
  series       = {{Matrix Biology}},
  title        = {{Cleavage of Cartilage Oligomeric Matrix Protein (COMP) by ADAMTS4 generates a neoepitope associated with osteoarthritis and other forms of degenerative joint disease}},
  url          = {{http://dx.doi.org/10.1016/j.matbio.2024.12.005}},
  doi          = {{10.1016/j.matbio.2024.12.005}},
  volume       = {{135}},
  year         = {{2025}},
}