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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.

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Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
Department of Molecular and Clinical Medicine, University of Liverpool, Liverpool L69 3BX, United Kingdom.
Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, United Kingdom.
Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
Department of Rheumatology, Aarhus University Hospital, 8200 Aarhus, Denmark.
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark


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.


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

[Available on 2020-10-18]

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