Summary:
Researchers have discovered that the drug LGK974, which inhibits the Wnt signaling pathway, shows promise in reversing excessive bone growth in sclerosteosis—a rare genetic disease that can cause hearing loss—offering a potential non-invasive alternative to high-risk surgery.

Key Takeaways:

  1. Targeted Innovation: LGK974 inhibits the Porcupine enzyme in the Wnt signaling pathway, significantly reducing bone overgrowth in sclerosteosis mouse models.
  2. Non-Invasive Promise: This treatment could replace invasive surgeries currently used to manage complications like hearing loss and increased intracranial pressure.
  3. Broader Impact: The findings may pave the way for treating other high bone mass disorders, though human trials are still needed to confirm safety and efficacy.

Sclerosteosis is a rare genetic disorder that causes excessive bone growth, leading to life-altering complications, including hearing loss and facial paralysis. In a promising new breakthrough, researchers have identified a drug called LGK974, which targets the Wnt signaling pathway by inhibiting the enzyme Porcupine. This treatment has shown the potential to effectively reduce bone mass and prevent further skeletal overgrowth in mice, offering hope for those suffering from this debilitating condition. Unlike the high-risk surgeries traditionally used to manage sclerosteosis, LGK974 presents a non-invasive alternative that could dramatically improve patient quality of life.

Sclerosteosis arises from mutations in the SOST gene, causing abnormally high bone mass and skeletal overgrowth, which can lead to severe health issues such as hearing loss and increased intracranial pressure. The key culprit behind this condition is the disruption of the Wnt signaling pathway, crucial for bone development. This groundbreaking study seeks to determine whether inhibiting Porcupine, a key regulator within this pathway, can reverse the bone overgrowth seen in this rare and serious disorder.

How LGK974 Works

This study was published (DOI: 10.1038/s41413-025-00406-3) in Bone Research, by a research team from the Skeletal Biology Group at the Royal Veterinary College, London, in collaboration with UCB Pharma, Slough, UK. Led by Dr Scott J. Roberts, the team investigates the impact of LGK974, a Porcupine inhibitor, on bone mass regulation in a sclerosteosis mouse model. By targeting the Wnt signaling pathway, LGK974 offers an innovative approach to combat the excessive bone growth seen in sclerosteosis. The research uncovers the potential of LGK974 as a promising treatment for this ultra-rare condition, providing an alternative to invasive surgeries commonly required for severe cases.

Preclinical Success in Mouse Models

Through both in vitro and in vivo experiments, the research team examined how LGK974 affects bone formation and the Wnt/β-catenin signaling pathway. The results were striking: LGK974 inhibited osteoblast activity and mineralization, mimicking the effects of sclerostin, a natural bone growth regulator. The drug successfully reduced excessive bone growth in the skull, vertebrae, and tibiae of Sost-/- mice, a model of sclerosteosis. Intriguingly, the drug exhibited a potential sexual dimorphic response, with male mice showing more pronounced benefits. The study also suggests that LGK974 not only prevents bone overgrowth but also preserves bone structure, reducing ossification. The potential for LGK974 to address the dangerous symptoms of sclerosteosis—such as hearing loss and intracranial pressure—could offer a significant improvement over the current surgical options available to patients.

“The ability to effectively inhibit bone overgrowth at sites of severe/fatal sclerosteosis pathologies, without obviously disrupting other physiological functions, is a monumental step forward,” says Dr Roberts, a senior researcher in the study. “The success of LGK974 in preclinical models marks a significant breakthrough, moving us closer to a viable, non-invasive treatment that could offer real relief for patients with this devastating condition.”

Potential for Broader Applications

The findings of this study hold great promise not only for sclerosteosis but also for other Wnt-related high bone mass conditions, such as Van Buchem disease. Targeting Porcupine provides a new avenue for treatment that could reduce reliance on high-risk surgeries. However, further clinical trials are necessary to confirm the drug’s safety and efficacy in humans, with attention to possible sex-based differences in response. 

This research highlights the importance of developing alternative, targeted therapies to manage bone overgrowth and improve the lives of patients who currently face limited treatment options and a lifetime of pain, discomfort, and debilitating symptoms.

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