Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection
| Autor: | Xiaochun Wei, Lei Wei, Gaetano J. Scuderi, Yang Zhang, Lewis S. Hanna, Shawn Browning |
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| Rok vydání: | 2017 |
| Předmět: |
Cartilage
Articular Male 0301 basic medicine Pathology medicine.medical_specialty lcsh:Diseases of the musculoskeletal system Anterior cruciate ligament Osteoarthritis Matrix metalloproteinase Andrology Random Allocation 03 medical and health sciences Targeted designed variants of A2M 0302 clinical medicine In vivo medicine Animals Anterior Cruciate Ligament Rats Wistar Aggrecan Rat ACLT OA model 030203 arthritis & rheumatology business.industry Cartilage PTOA medicine.disease Pregnancy-Associated alpha 2-Macroglobulins Bovine Cartilage Rats 3. Good health Disease Models Animal 030104 developmental biology medicine.anatomical_structure Immunohistochemistry lcsh:RC925-935 business Research Article |
| Zdroj: | Arthritis Research & Therapy, Vol 19, Iss 1, Pp 1-11 (2017) Arthritis Research & Therapy |
| ISSN: | 1478-6362 |
| DOI: | 10.1186/s13075-017-1363-4 |
| Popis: | Background The 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. Methods In 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. Results A2M 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. Conclusion The 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. |
| Databáze: | OpenAIRE |
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