Multi-functional Small Molecule for Regenerative Healing of Avascular Meniscus Tears: Modulation of Inflammation, Differentiation, and Multi-Tissue Crosstalk

Avascular meniscus tears are a major contributor to mechanical joint locking, compromised gait and function, and the initiation and progression of post-traumatic osteoarthritis.Unfortunately, the avascular meniscus tears hardly heal.Here, we report a novel small molecule, 4-PPBP, a sigma-1 receptor (σ1R) agonist, exhibiting significant potential to promote avascular meniscus healing by activating synovial mesenchymal stem cells (syMSCs) and modulating macrophage-regulated inflammation via multi-tissue crosstalk.In vitro, 4-PPBP promoted the proliferation and migration of meniscus cells and syMSCs, exhibited anti-inflammatory effects, and induced fibrochondrogenic differentiation.4-PPBP significantly promoted the healing of avascular meniscus tears ex vivo.In vivo, a single injection of 4-PPBP-loaded bioglue minimized meniscal gapping, with improved meniscus healing and gait performance.In contrast to the degenerative changes in the untreated control, 4-PPBP/bioglue application resulted in integrated fibrocartilaginous tissues.scRNA-seq and CellChat analyses revealed 4-PPBP-activated cell-cell communications leading to inflammatory regulation and cell differentiation.Macrophages showed a robust reduction in pro-inflammatory genes, and fibroblasts, chondrocytes, and fibrochondrocytes increased genes associated with differentiation and matrix synthesis in response to 4-PPBP.Anti-inflammatory cell-cell communication signals were significantly elevated between adipocytes and macrophages.Together, this study demonstrates the notable potential of 4-PPBP as a multi-functional therapeutic for avascular meniscus tears.