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

Carsten Scavenius; Emil Christian Poulsen; Ida B. Thøgersen; Margaret Roebuck; Simon Frostick; George Bou-Gharios; Kazuhiro Yamamoto; Bent Deleuran; Jan J. Enghild

doi:10.1074/jbc.RA119.008844

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

Carsten Scavenius, Emil Christian Poulsen, Ida B. Thøgersen, Margaret Roebuck, Simon Frostick, George Bou-Gharios, Kazuhiro Yamamoto, Bent Deleuran, Jan J. Enghild^*

^*Corresponding author for this work

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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.

Original language	English
Journal	Journal of Biological Chemistry
Volume	294
Issue	42
Pages (from-to)	15495-15504
Number of pages	10
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.RA119.008844
Publication status	Published - Oct 2019

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10.1074/jbc.RA119.008844

Matrix-degrading protease ADAMTS-5 cleaves inter-α-inhibitor and releases active heavy chain 2 in synovial fluids from arthritic patientsFinal published version, 1.31 MBLicence: Other

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Scavenius, C., Poulsen, E. C., Thøgersen, I. B., Roebuck, M., Frostick, S., Bou-Gharios, G., Yamamoto, K., Deleuran, B., & Enghild, J. J. (2019). Matrix-degrading protease ADAMTS-5 cleaves inter-αinhibitor and releases active heavy chain 2 in synovial fluids from arthritic patients. Journal of Biological Chemistry, 294(42), 15495-15504. https://doi.org/10.1074/jbc.RA119.008844

@article{943d3646b01e49eda97ea5710307fe3d,

title = "Matrix-degrading protease ADAMTS-5 cleaves inter-αinhibitor and releases active heavy chain 2 in synovial fluids from arthritic patients",

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.",

author = "Carsten Scavenius and Poulsen, {Emil Christian} and Th{\o}gersen, {Ida B.} and Margaret Roebuck and Simon Frostick and George Bou-Gharios and Kazuhiro Yamamoto and Bent Deleuran and Enghild, {Jan J.}",

year = "2019",

month = oct,

doi = "10.1074/jbc.RA119.008844",

language = "English",

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Scavenius, C , Poulsen, EC , Thøgersen, IB, Roebuck, M, Frostick, S, Bou-Gharios, G, Yamamoto, K, Deleuran, B & Enghild, JJ 2019, 'Matrix-degrading protease ADAMTS-5 cleaves inter-αinhibitor and releases active heavy chain 2 in synovial fluids from arthritic patients', Journal of Biological Chemistry, vol. 294, no. 42, pp. 15495-15504. https://doi.org/10.1074/jbc.RA119.008844

Matrix-degrading protease ADAMTS-5 cleaves inter-αinhibitor and releases active heavy chain 2 in synovial fluids from arthritic patients. / Scavenius, Carsten ; Poulsen, Emil Christian ; Thøgersen, Ida B. et al.
In: Journal of Biological Chemistry, Vol. 294, No. 42, 10.2019, p. 15495-15504.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Matrix-degrading protease ADAMTS-5 cleaves inter-αinhibitor and releases active heavy chain 2 in synovial fluids from arthritic patients

AU - Scavenius, Carsten

AU - Poulsen, Emil Christian

AU - Thøgersen, Ida B.

AU - Roebuck, Margaret

AU - Frostick, Simon

AU - Bou-Gharios, George

AU - Yamamoto, Kazuhiro

AU - Deleuran, Bent

AU - Enghild, Jan J.

PY - 2019/10

Y1 - 2019/10

N2 - 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.

AB - 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.

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U2 - 10.1074/jbc.RA119.008844

DO - 10.1074/jbc.RA119.008844

M3 - Journal article

C2 - 31484722

AN - SCOPUS:85073577017

SN - 0021-9258

VL - 294

SP - 15495

EP - 15504

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 42

ER -

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

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