Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment

Abstract

In our previous studies, we found that adult stem cells transfected with sex‐determining region Y‐box (SOX)‐9, ‐6 and ‐5 genes (SOX trio) enhanced chondrogenesis and suppressed the progression of osteoarthritis (OA). The inhibition of angiopoietin‐like 4 (ANGPT4) is known to reduce levels of cartilage damaging enzymes, such as, matrix metalloproteinases (MMPs). In this study, we designed nanoparticles comprising dexamethasone‐conjugated polyethylenimine (DEXPEI) complexed with minicircle plasmid (MC) harboring SOX duo (SOX‐9, ‐6) and ANGPTL4 small hairpin RNA (shANG) [MCSOX9/6/shANG] in the expectation that transfection of these nanoparticles would enhance chondrogenesis of stem cells and suppress inflammation in OA. Adipose‐derived stem cells (ADSCs) transfected with MCSOX9/6/shANG (MCSOX9/6/shANG‐tADSCs) showed significantly higher expressions of COL2 gene and protein than MCSOX9/6‐transfected ADSCs (MCSOX9/6‐tADSCs) during in vitro chondrogenesis while both enhanced chondrogenesis in the absence of growth factor addition as compared with negative controls. Furthermore, the expressions of MMP13 and MMP3 genes were significantly more diminished in MCSOX9/6/shANG‐tADSCs than in MCSOX9/6‐tADSCs. In vivo experiments using surgically‐induced OA rats showed MCSOX9/6/shANG‐tADSC‐treated rats had significantly lower levels of cyclooxygenase (COX‐2) and MMP13 in synovial fluids than MCSOX9/6‐tADSC‐treated rats, but no significant difference was observed between them in histological appearances. Both groups showed significantly less joint destruction than control groups did. These results demonstrate that dual functional nanoparticles containing SOX duo and ANGPT4 shRNA enhance chondrogenesis of ADSCs and suppress inflammation in OA. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:234–242, 2020.

miR-137 targets the inhibition of TCF4 to reverse the progression of osteoarthritis through the AMPK/NF-κB signaling pathway

“…The key to the treatment of OA is to expand phenotypic applicability, suppress inflammation and degrade joint tissues [7,8]. Although the current treatment methods for OA include mesenchymal stem cell therapy, nanoparticle therapy and infiltration therapy, the efficacy lacks effectiveness and applicability, so the pathogenesis of OA still needs to be clarified [9][10][11][12]. Therefore, it is of great significance for us to explore new targets to curb the progression of OA by understanding the molecular mechanism of OA.…”

Improving Cell Therapy Survival and Anabolism in Harsh Musculoskeletal Disease Environments

“…Aside from the use of differentiation signaling growth factors, some studies have induced differentiation through overexpression of SOX transcription factors in stem cells, which are known to be heavily involved in chondrogenesis. 126,127 Although SOX9 is known as the main chondrogenic transcription factor, in vivo delivery of cells has involved cells overexpressing both SOX9 and SOX6, as SOX6 enhances SOX9 activity. 128 One of the two studies, referenced in Table 5, uses ANGPTL4 shRNA along with SOX6 and SOX9 overexpression, as ANGPT4 has been shown to be higher in OA chondrocytes and induces MMP expression within them and stem cells.…”

“…128 One of the two studies, referenced in Table 5, uses ANGPTL4 shRNA along with SOX6 and SOX9 overexpression, as ANGPT4 has been shown to be higher in OA chondrocytes and induces MMP expression within them and stem cells. 127 Therefore, this approach may be more powerful as it is also counteracting negative genes associated with OA.…”

Multi‐Disciplinary Approaches for Cell‐Based Cartilage Regeneration

“…ASCs transfected with Sox gene‐harboring nanoparticles significantly enhanced chondrogenesis, showing higher expressions of the collagen type II gene and protein and suppression of matrix metalloproteinase 3 and 13 genes compared with control plasmid‐harboring nanoparticles. In vivo experiments using surgically induced OA in rats showed that Sox gene‐harboring nanoparticle transfected ASCs arrested the progression of OA in that model …”

“…In vivo experiments using surgically induced OA in rats showed that Sox gene-harboring nanoparticle transfected ASCs arrested the progression of OA in that model. 56 As a preclinical study to test the feasibility of Sox gene-based gene cell therapy to treat OA, the authors have developed Sox-6, 9-transfected human adipose stem cells ( SOX-6, 9 ASCs). These were tested for their effectiveness in arresting OA progression when IA injected in a surgically induced OA caprine model.…”