Intra-articular Transplantation Of Atsttrin-Engineered Mesenchymal Stem Cells Ameliorate Osteoarthritis Development

Background:Osteoarthritis (OA) remains as a great clinical challenge. Mechanical load, obesity, and improper sports all contribute to the development of OA. Although the incidence of osteoarthritis has reached up to10%among people over the age of60, however, few drugs are available. And most of the drugs are just painkillers. The pathology of OA includes cartilage surface damage, degradation of cartilage matrix, elevation of inflammatory level etc. Tumor necrosis factor TNF alpha (TNFa) is known as one of the factors caused cartilage degeneration. Atsttrin is a reconbimant protein from PGRN, which contains three effective fragments. It has higher affinity with TNFR and better effeciency in rheumatoid arthritis (RA) treatment than PGRN. On the other hand, stem cells are promising vehicle for gene delivery. Over-expression of Atsttrin in stem cells can avoid multiple injections of protein into joints for OA treatment Thus it may be a more rational way for OA treatment.Methods:Firstly, we developed genetically modified MSC that expressed recombinant Atstrrin (named as MSC-Atsttrin), and analyzed the expression levels of ADAMTS-5, MMP13and iNOS when co-cultured human chondrocytes with MSC-GFP/Atsttrin in vitro. Then we set up OA animal models by anterior cruciate ligament transection (ACLT) in vivo; and injected MSC-GFP/Atsttrin into the articular cavity1week post-surgery. Knee joints were collected4and8weeks after OA surgery for histological analysis, immunohistochemical staining and RNA purification.Results:We found that MSC-Atsttrin significantly suppressed the up-regulation of matrix proteases and inflammatory factors driven by TNFa in vitro. Intra-articular injection of MSC-Atsttrin prevented the progression of degenerative changes in OA mouse model in vivo, and the percentages of MMP13and ADAMTS-5positive cells were significantly reduced from94.33±4.7%to57.66±8.5%(p<0.001) and94.33±6.0%to16.67±3.0%(p<0.001), respectively.Conclusion:Our results indicated that suppression of TNFa activity is an effective strategy for OA treatment, and that intra-articular injection of MSC-Atsttrin could be a promising therapeutic modality.