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Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection

Authors
  • Zhang, Yang1
  • Wei, Xiaochun1
  • Browning, Shawn2
  • Scuderi, Gaetano2
  • Hanna, Lewis S.2
  • Wei, Lei1, 3
  • 1 the second hospital of the Shanxi Medical University, Department of Orthopedics, Taiyuan, China , Taiyuan (China)
  • 2 Cytonics Corporation, 6917 Vista Pkwy N., Suite 14, West Palm Beach, FL, 33411, USA , West Palm Beach (United States)
  • 3 Alpert Medical School of Brown University/Rhode Island Hospital, Department of Orthopedics, Providence, RI, USA , Providence (United States)
Type
Published Article
Journal
Arthritis Research & Therapy
Publisher
Springer Science and Business Media LLC
Publication Date
Jul 25, 2017
Volume
19
Issue
1
Identifiers
DOI: 10.1186/s13075-017-1363-4
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundThe study was performed to evaluate whether targeted alpha-2-macroglobulin (A2M) variants have a similar or enhanced function at wild-type (wt)-A2M to attenuate cartilage degeneration in vivo.MethodsIn and ex-vivo experiment, bovine cartilage explants (BCE) were incubated with TNF-α and IL-1β with or without wt-A2M or A2M variants. Cartilage catabolism was measured in culture supernatant by sulfated glycosaminoglycan (sGAG). In an in-vivo experiment, 2-month-old male Wistar rats (n = 77) were randomly divided into seven groups and treated with different doses of A2M or its variants by intra-articular injection at 24 hours and day 14 after anterior cruciate ligament transection (ACLT), receiving (1) ACLT/PBS; (2) ACLT/wt-A2M (0.153 mg); (3) ACLT/CYT-108 A2M (0.153 mg); (4) ACLT/CYT-108 A2M (0.077 mg); (5) ACLT/CYT-98 A2M (0.153 mg); (6) ACLT/CYT-98 A2M (0.077 mg); or (7) sham/PBS. The joints and synovial lavage were collected 8 weeks after surgery. Fluorescence molecular tomography was used to monitor inflammation in vivo using probes ProSense and MMPSense at 24 hours, and weeks 2, 4, and 6 after surgery. The cartilage damage was quantified using Osteoarthritis Research Society International score and matrix metalloproteinase (MMP)-3, -13, collagen (Col) X, Col 2, Runx2, and aggrecan (Acan) were detected by immunohistochemical analysis (IHC), ELISA, and RT-PCR.ResultsA2M variants inhibited catabolism in the BCE model by up to 200% compared with wt-A2M. ProSense and MMPSense were dramatically increased in all groups after surgery. Supplemental A2M or its variants reduced ProSense and MMPSense compared with the PBS treatment. Less cartilage damage, lower MMP-13 and Col 2 degraded product, and stronger Col 2 synthesis were detected in animals treated with A2M or its variants compared with PBS-treated animals. A2M and its variants enhanced Col 2 and Acan synthesis, and suppressed MMP-3, MMP-13, Runx2, and Col X production. A2M-108 variant demonstrated less cartilage damage compared with wt-A2M and A2M-98 variant.ConclusionThe targeted variants of A2M have a chondroprotective effect similar to wt-A2M. However, A2M-108 variant has enhanced function to attenuate cartilage degeneration compared with wt-A2M.

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