Polygonatum sibiricum polysaccharides regulate chondrocyte inflammation and metabolism via S100A9 inhibition-mediated autophagy promotion to ameliorate osteoarthritis.

BACKGROUND: Polygonatum sibiricum (P. sibiricum) polysaccharides (PSP), the main bioactive component in the roots of the medicinal and edible plant P. sibiricum, have been shown to exhibit strong anti-inflammatory activity. However, the role of PSP in alleviating osteoarthritis (OA)-related cartilage degeneration and the underlying mechanism-particularly its association with autophagy-remain elusive. This study aimed to investigate how PSP influences autophagy in the cartilage and chondrocytes, and to clarify the mechanisms involved.

METHODS: The molecular weight of PSP was measured using high-performance gel permeation chromatography (HPGPC), and the monosaccharide composition was analyzed using 1-phenyl-3-methyl-5-pyrazolone (PMP)-HPLC. Chondrocytes overexpressing p65/ S100 calcium-binding protein A9 (S100A9) were generated through the use of lentiviral vectors for gene overexpression. Autophagosomes of chondrocytes were detected by transmission electron microscope, and the expression levels of proteins associated with chondrocytes was identified through WB, immunofluorescence and ELISA. In vivo, the C57BL/6 mice model of OA was created by means of partial medial meniscectomy. Overexpressed lentivirus was injected into the joint cavity and transfected to articular cartilage, constructing an S100A9 overexpression model.

RESULTS: The results demonstrated that PSP can ameliorate interleukin-1β (IL-1β)-induced metabolic dysregulation and inflammatory responses in the chondrocyte extracellular matrix by enhancing chondrocyte autophagy, thereby restoring the impaired autophagy induced by IL-1β. RNA-seq analysis revealed that PSP inhibited the expression of S100A9 in IL-1β-induced chondrocytes. Further mechanistic evidence indicated that PSP promoted chondrocyte autophagy via the S100A9/nuclear factor κB (NF-κB) signaling pathway, thus alleviating chondrocyte inflammation and matrix metabolic disorders.

CONCLUSIONS: Both in vivo and in vitro evidence supports that PSP promotes chondrocyte autophagy by suppressing the S100A9/NF-κB pathway to achieve the outcome of OA improvement. This discovery highlights the potential of PSP as a valuable natural plant-derived compound in OA treatment.