Abstract. In the present study, the effects of chordin-like protein 1 (CHRDL1) overexpression, together with bone morphogenetic protein-4 (BMP-4) treatment, on the differentiation of rat spinal cord-derived neural stem cells (NSCs) was investigated. Adult rat spinal cord-derived NSCs were cultured in serum-free medium. The recombined eukaryotic expression vector pSecTag2/Hygro B-CHRDL1 was transfected into adult rat spinal cord-derived NSCs using a lipid-based transfection reagent and protein expression was assessed by western blot analysis. Differentiation of transfected NSCs following BMP-4 treatment was determined by immunocytochemistry. The percentage of microtubule-associated protein-2 (MAP-2)-positive cells in the BMP-4-treated (B) group was found to be significantly lower compared with that in the non-transfected control (N) group. The percentage of MAP-2-positive cells in the pSecTag2/Hygro B-CHRDL1-transfected, BMP-4-treated group was identified to be significantly higher compared with that in group B, however, no significant difference was observed between group N and the transfected, non-BMP-4-treated control group. The current study indicates that CHRDL1 protein antagonizes BMP-4 activity and induces spinal cord-derived NSCs to differentiate into neurons.

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Osteoarthritis (OA) is a joint disease characterized by articular cartilage degeneration, and no effective treatment is available. The OA classification has shifted from a cartilage‐only disease to a whole‐joint disease, and the synovial membrane plays an important role. Therefore, studies are needed to identify additional genes that regulate the pathological changes in the synovial membrane to develop a promising therapeutic strategy for OA. Here, we validated that the expression of forkhead box protein C1 (FoxC1) and β‐catenin was upregulated in OA synovial membranes and synovial fibroblasts (SFs). Gain‐ and loss‐of‐function studies revealed that FoxC1 overexpression promoted, whilst silencing inhibited OA synovial fibroblast (OASF) proliferation and pro‐inflammatory cytokine [interleukin 6 (IL‐6), interleukin 8 (IL‐8) and tumour necrosis factor‐α (TNF‐α)] production. FoxC1 overexpression increased β‐catenin mRNA, total and nuclear protein expression in OASFs and upregulated a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS‐5), fibronectin, matrix metalloproteinase 3 (MMP3) and matrix metalloproteinase 13 (MMP13) mRNA and total protein expression in OASFs. Conversely, FoxC1 knockdown reduced β‐catenin mRNA, total and nuclear protein expression in OASFs and reduced ADAMTS‐5, fibronectin, MMP3 and MMP13 mRNA and total protein expression in OASFs. β‐catenin mediates FoxC1‐induced pathological changes (proliferation, catabolic regulation and inflammation) in OASFs. MicroRNA‐200a‐3p (miR‐200a‐3p) binds to the 3′‐UTR of FoxC1 and mediates FoxC1 expression. Intra‐articular FoxC1‐specific siRNA transfection hindered OA development in mice. Therefore, our results demonstrate the key role FoxC1 plays in vivo and in vitro in OA synovial pathology, possibly identifying a potential novel therapeutic target for OA.

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