Proper regulation of Wnt signaling is critical for normal bone development and homeostasis. Mutations in several Wnt signaling components, which increase the activity of the pathway in the skeleton, cause high bone mass in human subjects 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 forehead bossing and mandibular overgrowth occur in almost all subjects. Treatments that would provide symptomatic relief in these subjects are limited. Porcupine-mediated palmitoylation is necessary for Wnt secretion and binding to the frizzled receptor. Chemical inhibition of porcupine is a highly selective method of Wnt signaling inhibition. We treated three different mouse models of high bone mass caused by aberrant Wnt signaling, including 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), at 3 months of age 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 subjects who suffer from these disorders and further establishes that the continued production of Wnts is necessary for sustaining high bone mass in these models.

Wnt 信号传导的正确调节对于正常的骨骼发育和体内平衡至关重要。多个 Wnt 信号成分的突变会增加骨骼中通路的活性，从而导致人类受试者和小鼠模型的骨量增加。骨量增加通常伴随着颅内压升高引起的严重头痛，这可能导致死亡，并因颅神经卡压而导致视力或听力丧失。此外，几乎所有受试者都会出现进行性前额隆起和下颌过度生长。能够缓解这些受试者症状的治疗方法是有限的。豪猪介导的棕榈酰化对于 Wnt 分泌和与卷曲受体的结合是必需的。豪猪的化学抑制是一种高度选择性的Wnt信号抑制方法。我们治疗了三种不同的由异常 Wnt 信号引起的高骨量小鼠模型，包括模拟硬化症的Sost功能丧失的纯合性，以及携带Lrp5不同点突变（相当于人类 G171V 和 A214V）的两种小鼠品系。 ，在 3 个月大时使用豪猪抑制剂 5-6 周。在所有三种模型中，治疗均显着减少了小梁骨和皮质骨量。这表明豪猪抑制对于缓解患有这些疾病的受试者的症状具有潜在的治疗作用，并进一步证实Wnt的持续产生对于在这些模型中维持高骨量是必要的。