AUTHORS
Bart Williams, Cassandra Diegel, Gabrielle Foxa, Mitchell McDonald, Zachary Madaj, Ina Kramer, Charles Moes, Sabine Guth, Jun Liu, Jennifer Harris, Michaela Kneissel
ABSTRACT
Proper regulation of Wnt signaling is critical for normal bone development and homeostasis. Mutations in several Wnt signaling components, which increase the pathway's activity in the skeleton, cause high bone mass in human patients and mouse models. Increased bone mass is often accompanied by severe headaches from increased intracranial pressure, which can lead to fatality and loss of vision or hearing due to the entrapment of cranial nerves. In addition, progressive bossing of the forehead and mandibular overgrowth occur in almost all patients. Treatments that would provide symptomatic relief in these patients are limited. Porcupine-mediated palmitoylation is necessary for Wnt secretion and binding to the Frizzled receptor. Chemical inhibition of porcupine is a highly selective inhibitor of all Wnt signaling. We treated three different mouse models of high bone mass caused by aberrant Wnt signaling: homozygosity for loss-of-function in SOST, which models Sclerosteosis, and two strains of mice carrying different point mutations in LRP5 (equivalent to human G171V and A214V) with porcupine inhibitors for 5–6 weeks. Treatment significantly reduced both trabecular and cortical bone mass in all three models. This demonstrates that porcupine inhibition is potentially therapeutic for symptomatic relief in patients who suffer from these disorders and further establishes that the continued production of Wnts is necessary for sustaining high bone mass in these models.