HSP90AA1 is a biomarker associated with defective autophagy in osteoarhritis

Abstract

Pellets were cultured for 14 days in serum-free chondrogenic medium (without dexamethasone). After 10 days of differentiation, MSCs were exposed to the OAs-cm from the same twelve individual donors. Cartilage formation was determined at day 14 by measuring sulfated glycosaminoglycan (sGAG) content. Results: Stimulation of the hIL6, hIL8 and hADAMTS5 promoter reporters with OAs-cm form twelve different patients resulted in an upregulation of promoter activity compared to control stimulation, whereas stimulation of the hWISP1 promoter reporter resulted in a down-regulation of the promoter activity compared to control. Interestingly, large heterogeneity was observed in the response of the promoter reporters between the OAs-cm from distinct patients with hIL6 (FC 33.9 ± 32.3), hIL8 (FC 32.2 ± 27.7), hADAMTS5 (FC 3.7 ± 2.4) and hWISP1 (FC 0.4 ± 0.24).Individual OAs-cm reduced sGAG content of differentiating MSCs by a range between 3% and 65%. Significant correlations were found between the fold change of the promoter activity and the percentage of inhibition on chondrogenesis. We observed a positive correlation with hIL6 (p¼0.01 and r¼0.67), hIL8 (p¼0.01 and r¼0.66) and with hADAMTS5 (p¼0.01 and r¼0.72), whereas a negative correlation was seen with hWISP1 (p¼0.003 and r¼-0.75). Conclusions: The current study demonstrates that we are able to measure profound heterogeneous patient-specific responses on different promoter reporters with OAs-cm from individual patients. Furthermore, significant correlations were found between the fold change of these promoter reporters and the inhibition of chondrogenic capacity of hMSCs, with positive correlations for hIL6, hIL8 and hADAMTS5 and a negative correlation with hWISP1. Our promoter constructs appear to be able to predict repair capacity of stem cells and could be of use for a personalized treatment strategy.

Discussion on the molecular mechanism of Duhuo Jisheng decoction in treating osteoarthritis based on network pharmacology and molecular docking

“…In 2016, a study found that targeted PIK3R1 inhibited the phosphorylation of Akt, mTOR, and S6 proteins in OA chondrocytes, thus inhibiting their survival and matrix synthesis of chondrocytes in OA. [ 38 ] This result indicated that PIK3R1 is a key target of chondrocyte materialism. Hsp90AA1 is a biomarker associated with defective autophagy in OA.…”