Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models

Abstract

BackgroundAtsttrin, 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.MethodsSurgically 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.ResultsHerein, 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1485-8) contains supplementary material, which is available to authorized users.

Increased serum levels of progranulin (PGRN) in patients with haemophilic arthropathy

“…Additionally, in control with absence of PGRN, grafts were at high risk of being damaged. As a result, PGRN is considered to be a promising prophylactic and therapeutic target for various arthritis associated diseases . Based on these studies, we hypothesize that PGRN may play a role in the pathogenesis and development of articular changes in patients suffering from haemophilia.…”

“…Furthermore, a PGRN‐deficient (PGRN −/− ) mouse model led to the spontaneous development of OA‐like pathological changes, which were mitigated after introduction of recombinant PGRN (rPGRN) . Wei et al demonstrated therapeutic effect of Atsttrin (protein composed of three tumour necrosis factor receptor (TNFR)‐binding fragments of progranulin) in inflammatory arthritis on murine models. Lau et al performed a study with transgenic living hyaline cartilage graft releasing progranulin.…”

Targeting tumor necrosis factor receptors in ankylosing spondylitis

“…Interestingly, PGRN functions as a physiological antagonist of TNFR1 and a potent agonist of TNFR2 (with approximately 600‐fold higher binding affinity to TNFR2 than TNF). PGRN and Atsttrin, an engineered peptide consisting of the domains and adjacent linker regions of PGRN responsible for interacting with TNFRs, appear to have strong anti‐inflammatory properties and were shown to mediate protective and anabolic effects in mouse models of osteoarthritis and inflammatory arthritis . Moreover, PGRN was shown to have protective and therapeutic effects in additional inflammatory disease models, including IBD, psoriasis, diabetes mellitus, systemic lupus erythematosus, and others .…”

“…PGRN and Atsttrin, an engineered peptide consisting of the domains and adjacent linker regions of PGRN responsible for interacting with TNFRs, appear to have strong anti-inflammatory properties and were shown to mediate protective and anabolic effects in mouse models of osteoarthritis and inflammatory arthritis. 36,91 Moreover, PGRN was shown to have protective and therapeutic effects in additional inflammatory disease models, including IBD, psoriasis, diabetes mellitus, systemic lupus erythematosus, and others. 92 A very recent publication has also demonstrated the ability of Atsttrin to inhibit TNF-mediated catabolism in a murine ex vivo model of intervertebral disk degeneration, supporting the protective effect of Atsttrin in TNF-driven inflammatory conditions impacting the axial skeleton.…”

Progranulin autoantibodies in systemic sclerosis and autoimmune connective tissue disorders: A preliminary study

“…15 In preliminary studies, Atsttrin proofed to have therapeutic effect in models of inflammatory arthritis, 14,15 inflammatory bowel disease, 16 and showed protective effects in bone healing and osteoarthritis. 17 In consideration of this possible proinflammatory role of PGRN-Abs and given the frequent occurrence of PGRN-Abs in the course of SLE, the present study was aimed to examine PGRN-Abs in serum of patients with systemic sclerosis and other autoimmune connective tissue disorders.…”