SPARCL1 targeting BST2 mediates meniscal inflammation and catabolic dysfunction by activating the NF-κB/P65 pathway

Meniscus injury is one of the most common musculoskeletal injuries, and its pathogenesis is associated with age, mechanical stress and inflammatory injury. However, the mechanism of meniscal degeneration remains unclear and this study aimed to investigate the role of SPARCL1 in meniscal degeneration.

Transcriptome sequencing of osteoarthritic/non-osteoarthritic meniscus from the Gene Expression Omnibus (GEO) was analysed. SPARCL1 expression was verified in anterior cruciate ligament transection (ACLT) mice and human degenerated meniscus. Mice were administered SPARCL1-knockdown lentiviruses via intra-articular injection after ACLT surgery. Extracellular matrix components and catabolic indicators were detected by immunohistochemistry and immunofluorescence. SPARCL1 was overexpressed in vitro, and the transcriptome was sequenced to explore the mechanism of SPARCL1 in meniscus degeneration. The role between SPARCL1 and BST2 was validated using fluorescence co-localization, molecular docking and Co-IP. Western blot, qPCR and immunofluorescence were used to detect catabolic indicators and NF-κB/P65 pathway after intervening with SPARCL1 expression in vitro.

SPARCL1 expression was upregulated in degenerated meniscus. Inhibiting SPARCL1 reduced the inflammatory levels, downregulated cellular catabolism and delayed meniscus degeneration in vivo. Overexpression of SPARCL1 upregulated the level of inflammation and enhanced cellular catabolic metabolism in meniscus cells in vitro. Sequencing identified BST2 as a downstream target and the binding of SPARCL1 to BST2 activated the NF-κB/P65 pathway, leading to meniscus degeneration.

SPARCL1 binding to BST2 activates the NF-κB/P65 pathway, exacerbating meniscus inflammation, enhancing catabolic metabolism and ultimately resulting in meniscus degeneration.