Panaxatriol exerts anti-senescence effects and alleviates osteoarthritis and cartilage repair fibrosis by targeting UFL1

Osteoarthritis is the most commmon degenerative joint disease which can
lead to disability eventually. However, there are currently no safe and
effective interventions available. Therefore, it is urgent to develop
effective drugs that can reduce cartilage damage and treat OA.With the in
vitro culturing of human cartilage explants and mouse OA model, it was
found that, panaxtriol, a natural small molecule drug, could promote
chondrocyte anabolism and inhibit catabolism. It could also reduce the
loss of cartilage matrix , decrease the subchondral osteosclerosis, and
relieve pain in mice. Eventually, it could delay the progression of OA.
Subsequently, the binding target of panaxtriol was found to be UFL1
through the target stability of drug affinity reaction (DARTS). The UFL1
knockout cell line was constructed using CRISPR-Cas9. Then, the regulation
of chondrocyte metabolism by panaxtriol was found to dependent on UFL1.
Transcriptome sequencing of UFL1 knockout cells were conducted. Through
differential gene analysis, GO analysis and KEGG analysis, it showed that
UFL1 was closely related to cell senescence. By using activators and
inhibitors of the signaling pathway, panaxtriol was proved that it can
inhibit chondrocyte senescence through UFL1/FOXO1/P21 and UFL1/NF-κB/SASPs
signaling pathways to delay the progression of OA. It also could inhibit
the formation of fibrocartilage during cartilage repair by UFL1/FOXO1/COL1
signaling pathway. Lastly, a sustained release system of panaxtriol was
constructed based on PLGA-PEG. Through drug sustained release, the
therapeutic effect was achieved while the number of intra-articular
injection was reduced, thereby alleviating joint swelling and joint
injury.