Catabolic Effects of Nell-1 Haploinsufficiency on Articular Cartilage in Murine Knee Joints

摘要

Contemporary therapeutic approaches for cartilage tissue engineering are flawed by significant functional heterogeneity and undesired side effects. A relatively novel growth factor, Nel1-like molecule-1 (Nell-1), has displayed a critical role in the pathogenesis of osteoarthritis in murine model and may hold promise in avoiding such pitfalls. In the current study, the Nell-1 haploinsufficient (Nell-1+/-) mouse model was further evaluated to the response of disruption of the Nell-1 axis on articular cartilage at different postnatal stages with a focus on its catabolic effects. The articular cartilage of both wild-type and Nell-1+/- knee joints at 1, 3, 7, and 10 months of age were first evaluated with H&E and Alcian Blue. MMP-13, ADAMTS5 Degraded Aggrecan were extensively examined by immunohistochemistry along with inflammation marker of IL-17, and anabolic marker collagen-2. Nell-1+/- mice showed depletion of matrix proteoglycans and alterations in articular cartilage and subchondral bone plate thickening in various degree starting on one month postnatal. Furthermore, these histological changes were associated with increased expression of MMP-13, ADAMTS5, Degraded Aggrecan and robust expression of IL-17. Thus, this study provided further supportive data to our hypothesis that lack of Nell-1 results in increased catabolic activity to articular cartilage and osteoarthritic alteration. Significantly, the similar observation in mice with cartilage specific knockout of Nell-1 strongly supports the crucial role of Nell-1 in the pathogenesis of osteoarthritis and therapeutic potential.