title: The amelioration of cartilage degeneration by ADAMTS-5 inhibitor delivered in a hyaluronic acid hydrogel.
abstract: 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-1β 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.
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Chen
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Shouan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Mu
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Jiadong
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Hu
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China. Electronic address: lupingzju@zju.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, China. Electronic address: hwoy@zju.edu.cn.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ouyang
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D053583:Interleukin-1beta / Q000494:pharmacology; D010003:Osteoarthritis / Q000188:drug therapy / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D053674:Aggrecans; D053583:Interleukin-1beta; D011480:Protease Inhibitors; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D006820:Hyaluronic Acid; D051722:ADAM Proteins
keywords: ADAMTS-5; Hydrogel; Osteoarthritis; Osteochondral defect