Effect of Nell-1 Haploinsufficiency on Articular Cartilage in Murine Hip Joints

Current available growth factors for cartilage tissue engineering are flawed by significant functional heterogeneity and side effects. A novel growth factor, Nell-1 (Nel1-like molecule-1), has recently been shown to hold promise for successful cartilage regeneration. NFATc2 (Nuclear factor of Activated T-Cells, Cytoplasmic 2) is a primary response gene for Nell-1 and has been shown to play crucial role in pathogenesis of osteoarthritis in mouse model. In this study we used a Nell-1 haploinsufficient (Nell-1+/-) mouse model to examine the effect of disturbance of Nell-1/NFATc2 axis on adult articular cartilage at different postnatal stages with focus on inflammation.The articular cartilage of wild-type and Nell-1+/- hip joints at 1, 3, 7, 10 and 12 month old were first evaluated with H&E and Alcian blue staining. Temporospatial pattern of transcription factor NFTAc2, and proinflammatory markers IL-6 and IL-17 were examined by immunohistochemistry. The data from immunohistochemistry at 1 and 3 month samples was validated by qPCR. Nell-1+/- mice showed depletion of matrix proteoglycans and alterations in articular cartilage and subchondral bone plate thicknesses. Significantly, this was associated with reduction of NFATc2 expression along with early-onset and robust expression of proinflammatory markers in adult articular cartilage and periarticular tissues. Current study shows an important mechanism of Nell-1 in regulating adult articular cartilage homeostasis, and inflammation in periarticular tissues via NFATc2 and/or inherent anti-inflammatory nature of Nell-1 molecule itself