NELL2 identified as a key regulator of bone formation and fat suppression

A recent study identifies Neural EGFL-like 2 (NELL2), a secreted protein, as a key regulator of bone homeostasis, offering potential therapeutic applications for osteoporosis. NELL2 promotes osteoblast differentiation and inhibits adipocyte formation in bone marrow stromal cells, addressing the bone remodeling imbalance in osteoporosis. The study further uncovers the molecular mechanism of NELL2's action, revealing its activation of the focal adhesion kinase (FAK)/AKT signaling pathway through interactions with Fibronectin 1 and integrins. NELL2's administration via adeno-associated virus (AAV) significantly improved bone density in osteoporotic mice, marking it as a promising target for clinical intervention in bone loss disorders.

Osteoporosis, a widespread bone disease affecting millions globally, is caused by an imbalance between bone resorption and formation. Current treatments primarily inhibit bone resorption, with limited options to stimulate bone formation. Aging and menopause exacerbate bone loss, highlighting the need for therapies that promote osteoblast activity. Neural EGFL-like 2 (NELL2), a protein previously studied in neural and reproductive systems, has emerged as a potential regulator of bone metabolism. Despite its role in other systems, its function in skeletal health remained unexplored-until now. Given these challenges, there is an urgent need to investigate NELL2's role in bone biology and its therapeutic potential for osteoporosis.

Published (DOI: 10.1038/s41413-025-00420-5) on April 11, 2025, in Bone Research, researchers from Tianjin Medical University revealed NELL2's critical role in bone homeostasis. The study found that NELL2 levels decrease in aged and osteoporotic models, whereas its overexpression enhances osteoblast differentiation and suppresses adipocyte formation

Using preosteoblast-specific knockout mice, the researchers confirmed that NELL2 is essential for maintaining bone mass. Mechanistically, NELL2 interacts with Fibronectin 1 and integrins to activate the FAK/AKT pathway. These findings position NELL2 as a promising therapeutic target for osteoporosis. A major discovery of the study is NELL2's dual function in bone metabolism: promoting osteoblast differentiation and inhibiting adipocyte formation. In loss-of-function experiments, NELL2-deficient mice displayed reduced bone mass and increased marrow fat, closely mimicking osteoporosis. In contrast, NELL2 overexpression in stromal cells increased osteogenic markers like Runx2 and osterix, while suppressing adipogenic markers like PPARγ.

One of the study's highlights is the identification of Fibronectin 1 (Fn1) as NELL2's binding partner, with the C-terminal FNI domain being crucial for this interaction. This complex activates the FAK/AKT signaling pathway, a well-known regulator of osteogenesis. Competitive inhibition experiments confirmed that disrupting NELL2-Fn1 binding eliminated NELL2's pro-osteogenic effects, confirming the pathway's specificity. Therapeutic potential was demonstrated in ovariectomized (OVX) mice, where NELL2-AAV delivery restored bone density and reduced marrow fat. This approach not only stimulated osteoblast activity but also influenced osteoclast function, suggesting systemic benefits. The translational impact of this study is notable as it addresses both bone formation and fat accumulation, offering a unique advantage over current osteoporosis treatments.

Dr. Baoli Wang, senior author of the study, stated, "NELL2 represents a paradigm shift in osteoporosis treatment by simultaneously enhancing bone formation and suppressing fat deposition in the marrow. Our findings reveal a previously unrecognized pathway that could lead to more effective therapies, especially for postmenopausal women and aging populations." The team's research connects molecular insights to clinical applications, offering new hope for addressing a disease with limited effective treatments.

The study's implications extend beyond basic science, offering a new avenue for osteoporosis treatment with NELL2-based therapies. AAV-mediated NELL2 delivery could address the root cause of osteoporosis-bone formation deficits-rather than merely slowing resorption. Future studies may explore NELL2 mimetics or small-molecule activators for clinical use. Additionally, NELL2's role in marrow adiposity may have implications for metabolic bone disorders. While challenges remain in optimizing delivery methods and assessing long-term safety, the proof-of-concept in mice presents a strong case for NELL2's therapeutic potential. With over 200 million people affected by osteoporosis globally, NELL2's dual-action mechanism positions it as a leading candidate in next-generation bone therapeutics.