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.
Highlights
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
We examine whether the engineered protein Atsttrin could protect against OA, as well as the molecular mechanisms involved, through the use of human primary chondrocytes in vitro alongside multiple models of OA implemented in genetically modified mice and Sprague–Dawley rats in vivo
Atsttrin rescues accelerated OA caused by PGRN deficiency Previously, we reported that PGRN is expressed in both human and mouse articular cartilage, and its level is elevated, relative to healthy controls in both human OA cartilage and in surgically induced OA model mice
Summary
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. Intra-articular delivery of PGRN protects against osteoarthritis (OA) progression. The mechanisms of OA development remain unclear and there are no available therapeutic agents that effectively prevent or arrest progression of the disease [2, 3]. The etiology of OA is still unclear, it is believed that tumor necrosis factor alpha (TNFα) exhibits an important effect in the pathological processes of OA [4]. Anti-TNFα drugs demonstrate preventative and therapeutic effect in various OA models as well as in clinical trials [6]. PGRN participates in many pathophysiological processes, including antiinflammation, tissue repair, and wound healing [9,10,11,12]
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