Intra-Articular Transplantation of Atsttrin-Transduced Mesenchymal Stem Cells Ameliorate Osteoarthritis Development

Abstract

Osteoarthritis (OA) remains an intractable clinical challenge. Few drugs are available for reversing this degenerative disease, although some promising candidates have performed well in preclinical studies. Tumor necrosis factor α (TNFα) has been identified as a crucial effector modulating OA pathogenesis. This study aimed to investigate the therapeutic effects of Atsttrin, a novel TNFα blocker, on OA treatment. We developed genetically modified mesenchymal stem cells (MSCs) that expressed recombinant Atsttrin (named as MSC-Atsttrin). Expression levels of ADAMTS-5, MMP13, and iNOS of human chondrocytes were analyzed when cocultured with MSC-GFP/Atsttrin. OA animal models were induced by anterior cruciate ligament transection, and MSC-GFP/Atsttrin were injected into the articular cavity 1 week postsurgery. The results showed that MSC-Atsttrin significantly suppressed TNFα-driven up-regulation of matrix proteases and inflammatory factors. Intra-articular injection of MSC-Atsttrin prevented the progression of degenerative changes in the surgically induced OA mouse model. Additionally, levels of detrimental matrix hydrolases were significantly diminished. Compared with nontreated OA samples at 8 weeks postsurgery, the percentages of MMP13- and ADAMTS-5-positive cells were significantly reduced from 91.33% ± 9.87% to 24.33% ± 5.7% (p < .001) and from 91.33% ± 7.1% to 16.67% ± 3.1% (p < .001), respectively. Our results thus indicated that suppression of TNFα activity is an effective strategy for OA treatment and that intra-articular injection of MSCs-Atsttrin could be a promising therapeutic modality.

Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis?

“…We have demonstrated that TNFR2 is critical for PGRN‐mediated protection in OA development and bone fracture healing . Another group recently showed that Atsttrin, an engineered protein composed of three TNFR‐binding fragments of PGRN, ameliorated OA development in a surgically induced mouse model . In brief, PGRN and its derived Atsttrin appear to exert their anti‐inflammatory and protective activities in OA by activation of the PGRN/TNFR2 protective/anabolic pathway, and by inhibition of TNFα/TNFR1 inflammatory/catabolic signaling …”

“…17,18,25 Another group recently showed that Atsttrin, an engineered protein composed of three TNFR-binding fragments of PGRN, ameliorated OA development in a surgically induced mouse model. 26 In brief, PGRN and its derived Atsttrin appear to exert their anti-inflammatory and protective activities in OA by activation of the PGRN/TNFR2 protective/anabolic pathway, 12,14,27-29 and by inhibition of TNFa/TNFR1 inflammatory/catabolic signaling. 17,26 Etanercept (Enbrel) is a fusion-soluble TNFR2 extracellular protein, and therefore inhibits both TNFa and PGRN.…”

The role of progranulin in arthritis

“…Notably, Xia et al . reported that intra‐articular transplantation of atsttrin‐transduced mesenchymal stem cells (MSC‐atsttrin) ameliorated OA development and confirmed the finding that TNF‐α level was increased in both mouse and human OA cartilage.…”

“…Additionally, this genetically engineered cell—MSC‐atsttrin—significantly decreased TNF‐α–induced expression of inflammatory molecules in human primary chondrocytes and effectively protected against OA development under the ACLT OA model. Specifically, MSC‐atsttrin significantly inhibited the loss of articular cartilage and downregulated matrix‐degrading enzymes, including MMP‐13 and ADAMTS‐5 …”

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

“…Studies indicated the engineered protein Atsttrin has similar anti‐inflammatory effects as PGRN. Furthermore, Atsttrin displays benefits over PGRN such as longer half‐life, higher efficacy, lower molecular weight, and most importantly no oncogenic effects . In preliminary studies, Atsttrin proofed to have therapeutic effect in models of inflammatory arthritis, inflammatory bowel disease, and showed protective effects in bone healing and osteoarthritis …”