According to the post Bone Research last month. Scientists have found that neural EGFL-like 2 (NELL2) plays a crucial role in maintaining bone health – potentially opening the door to a new generation of therapies that not only prevent bone loss, but actually stimulate new bone formation.
The study, conducted by scientists at Tianjin Medical University in China, shows that NELL2 levels decrease with age and menopause, is the increased risk of osteoporosis. When the researchers recovered NELL2 in laboratory mice with osteoporosis, the bone density and quality of the animals improved significantly.
In China alone, osteoporosis affects about 90 million people, and postmenopausal women are particularly vulnerable. This occurs when bone collapses beyond bone formation, leading to vulnerability and increasing the risk of fracture.
Dual-acting protein for bone health
What is particularly interesting about NELL2 is its dual beneficial effects. Proteins promote bone formation and inhibit the formation of fat cells in the bone marrow, which is the dual advantage of maintaining healthy bones.
In their experiments, the researchers found that mice lacking NELL2 in bone-forming cells had thinner bones with increased bone marrow fat, reflecting patterns in human osteoporosis. In contrast, when NELL2 was delivered to osteoporotic mice using gene therapy techniques, bone density increased and bone marrow fat decreased.
The researchers also found that postmenopausal women with normal bone density osteopenia or osteoporosis have lower levels of NELL2 in the blood, indicating a potential diagnostic application.
How NELL2 works in bone cells
This study found the precise molecular mechanism by which NELL2 affects osteocytes. This protein binds to another protein called fibronectin 1 on the cell surface and then activates a signaling pathway involving focal adhesion kinase (FAK) and protein kinase B (AKT), which is crucial for bone formation.
This signaling cascade will eventually increase the expression of key bone-forming genes while inhibiting adipocyte development genes. The researchers confirmed this approach through various experimental methods, including:
- Create mice with NELL2 specifically deleted in bone-forming cells
- Test the effect of NELL2 on cultured bone marrow cells
- Identify specific domains of interaction between NELL2 and Fibronectin 1
- NELL2 gene therapy delivered to mice through experimentally induced osteoporosis
Limitations of current treatment
The discovery is at a critical moment. Current treatment of osteoporosis is mainly focused on slowing bone decomposition rather than stimulating new bone formation. Most medications also have major side effects and do not fully restore bone health.
Anti-drug drugs such as bisphosphonates can effectively slow down bone loss but do not significantly increase bone formation. Several anabolic treatments that do stimulate bone growth often have limited treatment time and may lose effectiveness over time.
Can NELL2-based therapies fill this treatment gap? The study shows that they can provide fundamentally different approaches by targeting the human body’s natural bone building mechanism while preventing the accumulation of bone marrow fat.
From laboratory to treatment
Perhaps the most exciting discovery was when researchers used adeno-associated virus (AAV) technology to mice that had ovarian removal to simulate osteoporosis caused by menopause.
Two months after treatment, the bone structure of these mice improved significantly compared with the untreated controls. This treatment increases the number of bone-forming cells, reduces bone marrow adipocytes, and even reduces the number of bone-deformed cells, which completely reverses the hallmark of osteoporosis.
Dr. Baoli Wang, senior author of the study, highlighted the significance of these findings: “NELL2 represents a paradigm shift in osteoporosis treatment by simultaneously enhancing bone formation and suppressing fat deposit 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 road ahead
Although these results are promising, there are still some problems before NELL2-based treatment reaches the patient. Researchers must determine the best delivery method, dose and safety for human use. Gene therapy methods like those used in research are developing rapidly, but are still facing regulatory barriers.
In addition, the long-term effects of NELL2 treatment require further investigation. Will the benefits last after treatment? In other tissues, will other tissues whose NELL2 naturally expresses have unexpected side effects, such as the brain or genital organs?
Despite these open questions, the discovery of the role of NELL2 in skeletal biology represents our understanding of osteoporosis. More than 200 million people are affected by global impacts and limited effective therapies, and the potential of therapeutics that can actually rebuild bones rather than just prevent further loss can change how we manage this common and debilitating condition.
For millions of fractures, pain and disabilities that suffer from osteoporosis every year, this protein may provide something that current treatments do not offer – not only stopping bone loss, but also restores bone strength and quality.
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