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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

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Titel: Cleavage of Cartilage Oligomeric Matrix Protein (COMP) by ADAMTS4 generates a neoepitope associated with osteoarthritis and other forms of degenerative joint disease
Autoren: de Groot, Rens, Folgado, Patricia Badía, Yamamoto, Kazuhiro, Martin, Daniel R, Koch, Christopher D, Debruin, Danielle, Blagg, Sophie, Minns, Alexander F, Bhutada, Sumit, Ahnström, Josefin, Larkin, Jonathan, Aspberg, Anders, Önnerfjord, Patrik, Apte, Suneel S, Santamaria, Salvatore
Weitere Verfasser: Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Rheumatology, Molecular Skeletal Biology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Reumatologi och molekylär skelettbiologi, Molekylär skelettbiologi, Originator, Lund University, Profile areas and other strong research environments, Lund University Profile areas, LU Profile Area: Proactive Ageing, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Lunds universitets profilområden, LU profilområde: Proaktivt åldrande, Originator
Quelle: Matrix Biology. 135:106-124
Schlagwörter: Medical and Health Sciences, Clinical Medicine, Medicin och hälsovetenskap, Klinisk medicin
Beschreibung: 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 fluidof 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.
Zugangs-URL: https://doi.org/10.1016/j.matbio.2024.12.005
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  Data: Cleavage of Cartilage Oligomeric Matrix Protein (COMP) by ADAMTS4 generates a neoepitope associated with osteoarthritis and other forms of degenerative joint disease
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  Data: Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Rheumatology, Molecular Skeletal Biology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Reumatologi och molekylär skelettbiologi, Molekylär skelettbiologi, Originator<br />Lund University, Profile areas and other strong research environments, Lund University Profile areas, LU Profile Area: Proactive Ageing, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Lunds universitets profilområden, LU profilområde: Proaktivt åldrande, Originator
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  Data: 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 fluidof 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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