NELL2, a novel osteoinductive factor, regulates osteoblast differentiation and bone homeostasis through fibronectin 1/integrin-mediated FAK/AKT signaling

Neural EGFL-like 2 (NELL2) is a secreted protein known for its regulatory functions in the nervous and reproductive systems, yet its role in bone biology remains unexplored. In this study, we observed that NELL2 was diminished in the bone of aged and ovariectomized (OVX) mice, as well as in the serum of osteopenia and osteoporosis patients. In vitro loss-of-function and gain-of-function studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells. In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice. Mechanistically, NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1 (Fn1). Moreover, we found that NELL2 activated the focal adhesion kinase (FAK)/AKT signaling pathway through Fn1/integrin β1 (ITGB1), leading to the promotion of osteogenesis and the inhibition of adipogenesis. Notably, administration of NELL2-AAV was found to ameliorate bone loss in OVX mice. These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis, suggesting its potential as a therapeutic target for managing osteoporosis.