Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models
Abstract Background Atsttrin, an engineered protein composed of three tumor necrosis factor receptor (TNFR)-binding fragments of progranulin (PGRN), shows therapeutic effect in multiple murine models of inflammatory arthritis . Additionally, intra-articular delivery of PGRN protects against osteoart...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-12-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-017-1485-8 |
| _version_ | 1819183128307040256 |
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| author | Jian-lu Wei Wenyu Fu Yuan-jing Ding Aubryanna Hettinghouse Matin Lendhey Ran Schwarzkopf Oran D. Kennedy Chuan-ju Liu |
| author_facet | Jian-lu Wei Wenyu Fu Yuan-jing Ding Aubryanna Hettinghouse Matin Lendhey Ran Schwarzkopf Oran D. Kennedy Chuan-ju Liu |
| author_sort | Jian-lu Wei |
| collection | DOAJ |
| description | Abstract Background Atsttrin, an engineered protein composed of three tumor necrosis factor receptor (TNFR)-binding fragments of progranulin (PGRN), shows therapeutic effect in multiple murine models of inflammatory arthritis . Additionally, intra-articular delivery of PGRN protects against osteoarthritis (OA) progression. The purpose of this study is to determine whether Atsttrin also has therapeutic effects in OA and the molecular mechanisms involved. Methods Surgically induced and noninvasive rupture OA models were established in mouse and rat, respectively. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry, and ELISA. Additionally, expressions of pain-related markers, degenerative factors, and anabolic and catabolic markers known to be involved in OA were analyzed. Furthermore, the anabolic and anti-catabolic effects and underlying mechanisms of Atsttrin were determined using in-vitro assays with primary chondrocytes. Results Herein, we found Atsttrin effectively prevented the accelerated OA phenotype associated with PGRN deficiency. Additionally, Atsttrin exhibited a preventative effect in OA by protecting articular cartilage and reducing OA-associated pain in both nonsurgically induced rat and surgically induced murine OA models. Mechanistic studies revealed that Atsttrin stimulated TNFR2-Akt-Erk1/2-dependent chondrocyte anabolism, while inhibiting TNFα/TNFR1-mediated inflammatory catabolism. Conclusions These findings not only provide new insights into the role of PGRN and its derived engineered protein Atsttrin in cartilage homeostasis as well as OA in vivo, but may also lead to new therapeutic alternatives for OA as well as other relative degenerative joint diseases. |
| first_indexed | 2024-12-22T22:57:06Z |
| format | Article |
| id | doaj.art-b78535daaeb2435b973d5ddfc2bba91c |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-22T22:57:06Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-b78535daaeb2435b973d5ddfc2bba91c2022-12-21T18:09:47ZengBMCArthritis Research & Therapy1478-63622017-12-0119111410.1186/s13075-017-1485-8Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat modelsJian-lu Wei0Wenyu Fu1Yuan-jing Ding2Aubryanna Hettinghouse3Matin Lendhey4Ran Schwarzkopf5Oran D. Kennedy6Chuan-ju Liu7Department of Orthopaedic Surgery, New York University Medical CenterDepartment of Orthopaedic Surgery, New York University Medical CenterDepartment of Orthopaedic Surgery, New York University Medical CenterDepartment of Orthopaedic Surgery, New York University Medical CenterDepartment of Orthopaedic Surgery, New York University Medical CenterDepartment of Orthopaedic Surgery, New York University Medical CenterDepartment of Orthopaedic Surgery, New York University Medical CenterDepartment of Orthopaedic Surgery, New York University Medical CenterAbstract Background Atsttrin, an engineered protein composed of three tumor necrosis factor receptor (TNFR)-binding fragments of progranulin (PGRN), shows therapeutic effect in multiple murine models of inflammatory arthritis . Additionally, intra-articular delivery of PGRN protects against osteoarthritis (OA) progression. The purpose of this study is to determine whether Atsttrin also has therapeutic effects in OA and the molecular mechanisms involved. Methods Surgically induced and noninvasive rupture OA models were established in mouse and rat, respectively. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry, and ELISA. Additionally, expressions of pain-related markers, degenerative factors, and anabolic and catabolic markers known to be involved in OA were analyzed. Furthermore, the anabolic and anti-catabolic effects and underlying mechanisms of Atsttrin were determined using in-vitro assays with primary chondrocytes. Results Herein, we found Atsttrin effectively prevented the accelerated OA phenotype associated with PGRN deficiency. Additionally, Atsttrin exhibited a preventative effect in OA by protecting articular cartilage and reducing OA-associated pain in both nonsurgically induced rat and surgically induced murine OA models. Mechanistic studies revealed that Atsttrin stimulated TNFR2-Akt-Erk1/2-dependent chondrocyte anabolism, while inhibiting TNFα/TNFR1-mediated inflammatory catabolism. Conclusions These findings not only provide new insights into the role of PGRN and its derived engineered protein Atsttrin in cartilage homeostasis as well as OA in vivo, but may also lead to new therapeutic alternatives for OA as well as other relative degenerative joint diseases.http://link.springer.com/article/10.1186/s13075-017-1485-8AtsttrinProgranulinTNFαTNFR2TNFR1Osteoarthritis |
| spellingShingle | Jian-lu Wei Wenyu Fu Yuan-jing Ding Aubryanna Hettinghouse Matin Lendhey Ran Schwarzkopf Oran D. Kennedy Chuan-ju Liu Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models Arthritis Research & Therapy Atsttrin Progranulin TNFα TNFR2 TNFR1 Osteoarthritis |
| title | Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models |
| title_full | Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models |
| title_fullStr | Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models |
| title_full_unstemmed | Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models |
| title_short | Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models |
| title_sort | progranulin derivative atsttrin protects against early osteoarthritis in mouse and rat models |
| topic | Atsttrin Progranulin TNFα TNFR2 TNFR1 Osteoarthritis |
| url | http://link.springer.com/article/10.1186/s13075-017-1485-8 |
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