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

Autor:	Scavenius C; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark., Poulsen EC; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark., Thøgersen IB; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark., Roebuck M; Department of Molecular and Clinical Medicine, University of Liverpool, Liverpool L69 3BX, United Kingdom., Frostick S; Department of Molecular and Clinical Medicine, University of Liverpool, Liverpool L69 3BX, United Kingdom., Bou-Gharios G; Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, United Kingdom., Yamamoto K; Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, United Kingdom., Deleuran B; Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.; Department of Rheumatology, Aarhus University Hospital, 8200 Aarhus, Denmark., Enghild JJ; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark jje@mbg.au.dk.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2019 Oct 18; Vol. 294 (42), pp. 15495-15504. Date of Electronic Publication: 2019 Sep 04.
DOI:	10.1074/jbc.RA119.008844
Abstrakt:	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. (© 2019 Scavenius et al.)
Databáze:	MEDLINE
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