Characterising skull pathologies in the Sost -deficient mouse for preclinical evaluation of sclerosteosis treatments

Le résumé fourni par la source

Facial paralysis, hearing loss and potentially lethal raised intracranial pressure are primary symptoms of sclerosteosis, an ultra-rare, autosomal recessive high bone mass (HBM) condition that predominantly manifests in skull pathologies. Non-invasive treatment remains an unmet clinical need. Recently, PORCN inhibition has been shown to reduce bone mass in young Sost-deficient (Sost-/-) mice. In this paper, we characterised sclerosteosis skull pathologies at later adult stages using a Sost-/- mouse model, with a view to drug efficacy evaluation. This revealed that male and female 9-month-old Sost-/- mice recapitulate the skull overgrowth and neural impingement of human sclerosteosis. We observed that the foramen magnum was narrowed in Sost-/- mice, and that parietal bone mass and thickness were significantly elevated. Otosclerosis was apparent, and animals exhibited significant hearing loss at age 8-9 months. Further, prominent mandibles highlighted hyperostosis in the jaw. Sexual dimorphism was also evident in the Sost-/- mice, underscoring the importance of including both sexes in HBM studies. This study provides new insight into Sost-/--skull-related pathology and further validates Sost-/- mice as a valuable model for investigating potential treatments for sclerosteosis and other HBM related conditions.

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