The Wnt signaling pathway (pictured) is crucial to the bone development process. When the process goes wrong, as in the case of the rare genetic disorder known as sclerosteosis – which arises from mutations in the SOST gene – the results invariably mean hearing loss, a concomitant of other likely horrors such as facial paralysis, intercranial pressure, and a frequent complication: loss of vision. Correction attempts involve surgery with high risks.

Is there a better way to limit the abnormally high bone mass and skeletal overgrowth resulting from this gene mutation which, although very rare, has been reported mainly in Afrikaners of Dutch descent living in South Africa?

 

Targeting Porcupine, a crucial enzyme, could lead to relief for sclerosteosis patients

 

Researchers from the Skeletal Biology Group at the Royal Veterinary College, London, in collaboration with UCB Pharma, Slough, UK. Led by Dr. Scott J. Roberts, have been studying whether the inhibition of Porcupine, an enzyme involved in the Wnt signaling pathway, could provide an innovative, non-invasive approach to combat the excessive bone growth seen in sclerosteosis.

And it seems that the research team has been able to report a successful experiment (in the journal Bone Research). In mice studies, the treatment has shown the potential to effectively reduce bone mass and prevent further skeletal overgrowth.

The drug used is called LGK974. And its observed effects suggest that LGK974 not only prevents bone overgrowth but also preserves bone structure, reducing ossification.

Dr. Scott J. Roberts, a senior researcher in the study, called it “a monumental step forward”. Further clinical trials are necessary to confirm the drug’s safety and efficacy in humans, with attention to possible sex-based differences in response; among mice, there was a notably better response in the male subjects. But LGK974 could have a role in developing alternative, targeted therapies to manage bone overgrowth and improve the lives of patients, not just in sclerosteosis but also in other bone mass conditions, such as Van Buchem disease.

Source: Bone Research