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J Biol Chem. 2019 Oct 18;294(42):15495-15504. doi: 10.1074/jbc.RA119.008844. Epub 2019 Sep 4.

Matrix-degrading protease ADAMTS-5 cleaves inter-α-inhibitor and releases active heavy chain 2 in synovial fluids from arthritic patients.

Author information

1
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
2
Department of Molecular and Clinical Medicine, University of Liverpool, Liverpool L69 3BX, United Kingdom.
3
Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, United Kingdom.
4
Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
5
Department of Rheumatology, Aarhus University Hospital, 8200 Aarhus, Denmark.
6
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark jje@mbg.au.dk.

Abstract

Destruction of the cartilage matrix in joints is an important feature of arthritis. Proteolytic degradation of cartilage glycoproteins can contribute to the loss of matrix integrity. Human inter-α-inhibitor (IαI), which stabilizes the extracellular matrix, is composed of the light-chain serine proteinase inhibitor bikunin and two homologous heavy chains (HC1 and HC2) covalently linked through chondroitin 4-sulfate. Inflammation promotes the transfer of HCs from chondroitin 4-sulfate to hyaluronan by tumor necrosis factor-stimulated gene-6 protein (TSG-6). This reaction generates a covalent complex between the heavy chains and hyaluronan that can promote leukocyte invasion. This study demonstrates that both IαI and the HC-hyaluronan complex are substrates for the extracellular matrix proteases ADAMTS-5 and matrix metalloprotease (MMP) -3, -7, and -13. The major cleavage sites for all four proteases are found in the C terminus of HC2. ADAMTS-5 and MMP-7 displayed the highest activity toward HC2. ADAMTS-5 degradation products were identified in mass spectrometric analysis of 29 of 33 arthropathic patients, indicating that ADAMTS-5 cleavage occurs in synovial fluid in arthritis. After cleavage, free HC2, together with TSG-6, is able to catalyze the transfer of heavy chains to hyaluronan. The release of extracellular matrix bound HC2 is likely to increase the mobility of the HC2/TSG-6 catalytic unit and consequently increase the rate of the HC transfer reaction. Ultimately, ADAMTS-5 cleavage of HC2 could alter the physiological and mechanical properties of the extracellular matrix and contribute to the progression of arthritis.

KEYWORDS:

ADAMTS; arthritis; bikunin; extracellular matrix protein; hyaluronan; inter-α-inhibitor; metalloprotease

PMID:
31484722
PMCID:
PMC6802519
[Available on 2020-10-18]
DOI:
10.1074/jbc.RA119.008844

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