The amelioration of cartilage degeneration by ADAMTS-5 inhibitor delivered in a hyaluronic acid hydrogel

被引：65

作者：

Chen, Pengfei ^{[1
,2
]}

Zhu, Shouan ^{[1
,2
]}

Wang, Yanyan ^{[1
,2
]}

Mu, Qin ^{[1
,2
]}

Wu, Yan ^{[1
,2
]}

Xia, Qingqing ^{[1
,2
]}

Zhang, Xiaolei ^{[1
,2
]}

Sun, Heng ^{[1
,2
]}

Tao, Jiadong ^{[1
,2
]}

Hu, Hu ^{[3
]}

Lu, Ping ^{[1
,2
]}

Ouyang, Hongwei ^{[1
,2
]}

机构：

[1] Zhejiang Univ, Sch Med, Ctr Stem Cell & Tissue Engn, Hangzhou 310058, Zhejiang, Peoples R China

[2] Zhejiang Prov Key Lab Tissue Engn & Regenerat Med, Hangzhou, Zhejiang, Peoples R China

[3] Zhejiang Univ, Sch Med, Dept Pathol & Pathophysiol, Hangzhou 310058, Zhejiang, Peoples R China

来源：

BIOMATERIALS | 2014年 / 35卷 / 09期

基金：

国家高技术研究发展计划(863计划);

关键词：

Hydrogel; ADAMTS-5; Osteochondral defect; Osteoarthritis; REPAIR-SOCIETY ICRS; AGGRECANASE-2; INHIBITORS; BIOLOGICAL EVALUATION; CHONDROITIN SULFATE; OSTEOARTHRITIS; DERIVATIVES; DEGRADATION; MODEL; CHONDROGENESIS; ADHESIONS;

D O I：

10.1016/j.biomaterials.2013.12.076

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

Degradation of proteoglycan is the key early event in the development of osteoarthritis (OA). The aggrecanase ADAMTS-5 has been identified as the major enzyme responsible for the degradation and thus is an attractive therapeutic target for OA. However, currently there is no report on using an ADAMTS-5 inhibition strategy for OA treatment. The present study aimed to investigate the synergic effect of combining an ADAMTS-5 inhibitor (114810) with a hyaluronic acid hydrogel (HAX) for OA therapeutics. Two OA models were induced by surgically creating an osteochondral defect or removing the anterior cruciate ligament (ACL) in Sprague-Dawley rats. Human OA cartilage was obtained from total joint replacement patients. Both human and rat OA cartilage showed marked proteoglycan loss with significantly increased ADAMTS-5 expression. The effectiveness of ADAMTS-5 inhibition by 114810 was confirmed by a cartilage explants assay in vitro, which showed that the 114810 halted the aggrecanase-mediated (374)ARGS neoepitope released from aggrecan induced by IL-1 beta stimulation. The in vivo effect of ADAMTS-5 inhibition was assessed by the articular injection of HAX with 114810 into OA knee joints. Evaluated eight weeks after injection, 114810 with HAX significantly promoted the in vivo cartilage healing in the osteochondral defect model, and prevented the progression of degenerative changes in the ACL model. Our results confirmed that ADAMTS-5 is an effective target for OA treatment, and the intra-articular injection of an ADAMTS-5 inhibitor within HAX gel could be a promising strategy for OA treatment. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：2827 / 2836

页数：10

共 45 条

[11] Protective effect of lentivirus-mediated siRNA targeting ADAMTS-5 on cartilage degradation in a rat model of osteoarthritis [J].

Chu, Xiangyu ;

You, Hongbo ;

Yuan, Xuefeng ;

Zhao, Wenbin ;

Li, Wenkai ;

Guo, Xin .

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 2013, 31 (05) :1222-1228

[12] Discovery of Highly Potent and Selective Small Molecule ADAMTS-5 Inhibitors That Inhibit Human Cartilage Degradation via Encoded Library Technology (ELT) [J].

Deng, Hongfeng ;

O'Keefe, Heather ;

Davie, Christopher P. ;

Lind, Kenneth E. ;

Acharya, Raksha A. ;

Franklin, G. Joseph ;

Larkin, Jonathan ;

Matico, Rosalie ;

Neeb, Michael ;

Thompson, Monique M. ;

Lohr, Thomas ;

Gross, Jeffrey W. ;

Centrella, Paolo A. ;

O'Donovan, Gary K. ;

Bedard, Katie L. ;

van Vloten, Kurt ;

Mataruse, Sibongile ;

Skinner, Steven R. ;

Belyanskaya, Svetlana L. ;

Carpenter, Tiffany Y. ;

Shearer, Todd W. ;

Clark, Matthew A. ;

Cuozzo, John W. ;

Arico-Muendel, Christopher C. ;

Morgan, Barry A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (16) :7061-7079

[13] A DIRECT SPECTROPHOTOMETRIC MICRO-ASSAY FOR SULFATED GLYCOSAMINOGLYCANS IN CARTILAGE CULTURES [J].

FARNDALE, RW ;

SAYERS, CA ;

BARRETT, AJ .

CONNECTIVE TISSUE RESEARCH, 1982, 9 (04) :247-248

[14] N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) [J].

Gilbert, Adam M. ;

Bursavich, Matthew G. ;

Lombardi, Sabrina ;

Georgiadis, Katy E. ;

Reifenberg, Erica ;

Flannery, Carl R. ;

Morris, Elisabeth A. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (24) :6454-6457

[15] 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 [J].

Gilbert, Adam M. ;

Bursavich, Matthew G. ;

Lombardi, Sabrina ;

Georgiadis, Katy E. ;

Reifenberg, Erica ;

Flannery, Carl R. ;

Morris, Elisabeth A. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (05) :1189-1192

[16] Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice [J].

Glasson, SS ;

Askew, R ;

Sheppard, B ;

Carito, BA ;

Blanchet, T ;

Ma, HL ;

Flannery, CR ;

Kanki, K ;

Wang, E ;

Peluso, D ;

Yang, ZY ;

Majumdar, MK ;

Morris, EA .

ARTHRITIS AND RHEUMATISM, 2004, 50 (08) :2547-2558

[17] Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis [J].

Glasson, SS ;

Askew, R ;

Sheppard, B ;

Carito, B ;

Blanchet, T ;

Ma, HL ;

Flannery, CR ;

Peluso, D ;

Kanki, K ;

Yang, ZY ;

Majumdar, MK ;

Morris, EA .

NATURE, 2005, 434 (7033) :644-648

[18] The role of the cartilage matrix in osteoarthritis [J].

Heinegard, Dick ;

Saxne, Tore .

NATURE REVIEWS RHEUMATOLOGY, 2011, 7 (01) :50-56

[19] Stem Cells and Cartilage Development: Complexities of a Simple Tissue [J].

Hollander, Anthony P. ;

Dickinson, Sally C. ;

Kafienah, Wael .

STEM CELLS, 2010, 28 (11) :1992-1996

[20] Injectable in situ cross-linking hydrogels for local antifungal therapy [J].

Hudson, Sarah P. ;

Langer, Robert ;

Fink, Gerald R. ;

Kohane, Daniel S. .

BIOMATERIALS, 2010, 31 (06) :1444-1452

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