NUMB attenuates post-traumatic osteoarthritis by inhibitingBTRC and inactivating NF-κB pathway

Background: Post-traumatic osteoarthritis (PTOA) is closely related to the inflammatory response caused by mechanical injury, leading to joint degeneration. Herein, we aim to evaluate the role and the underlying mechanism of NUMB in PTOA progression. Methods Anterior cruciate ligament transection (ACLT)-induced rats and LPS-treated chondrocytes were used as in vivo and in vitro models of PTOA, respectively. NUMB overexpression plasmid (pcDNA-NUMB) were administered by intra-articular injection in PTOA model rats, and safranin O-fast green staining, the Osteoarthritis Research Society International (OARSI) Scoring System, and HE staining were used to evaluate the severity of cartilage damage. The secretion of inflammatory cytokines (TNF-α, IL-1β, IL-6) and chondrocyte-specific markers (MMP13, COL2A1) was detected by ELISA. Cell viability and apoptosis were evaluated by MTT assay and TUNEL staining. Results The expression of NUMB was lower expressed in ACLT-induced PTOA rats and LPS-treated chondrocytes. NUMB overexpression enhanced cell viability and reduced cell apoptosis, inflammation and cartilage degradation in chondrocytes stimulated by IL-1β. NUMB bound with BTRC to inhibiting p-IκBα expression, resulting in NF-κB pathway inactivation. BTRC overexpression reversed the promoting effect of NUMB overexpression on cell viability and the inhibitory effects of NUMB overexpression on apoptosis, inflammation and cartilage degradation in LPS-induced chondrocytes. Besides, overexpression of NUMB alleviated articular cartilage damage by repression of inflammation and cartilage degradation in ACLT-induced PTOA rats. Conclusion Our data indicated that NUMB negatively regulates BTRC regulated PTOA progression by BTRC/NF-κB pathway, which may be a viable therapeutic target in PTOA.