Dreyer Timothy J, Keen Jacob A C, Wells Leah M, Hopkinson Mark, Orriss Isabel R, Holdsworth Gill, Pitsillides Andrew A, Roberts Scott J
Skeletal Biology Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, UK.
UCB Pharma, Slough, UK.
Bone Res. 2025 Apr 7;13(1):44. doi: 10.1038/s41413-025-00406-3.
Sclerosteosis, an ultra-rare disorder characterised by high bone mass (HBM) and skeletal overgrowth, leads to facial paralysis, hearing loss and raised intracranial pressure, which is currently managed only through high-risk surgery. Sclerosteosis is caused by SOST mutations and loss of functional sclerostin, a protein that suppresses osteogenesis by antagonising Wnt/β-catenin signalling. Herein, using in vitro and in vivo approaches, we explore whether LGK974, another potent Wnt inhibitor that targets porcupine (PORCN, Wnt-specific acyltransferase), is a promising sclerosteosis therapeutic. In vitro assays showed that 100 nmol/L LGK974 significantly reduced osteoblast alkaline phosphatase (ALP) activity/mineralisation, decreased Wnt/osteoblast marker (Axin2, Runx2 and Ocn) expression, and downregulated ossification and the Wnt signalling pathway, without affecting osteoclast numbers/resorption. To assess in vivo effects, 6-week-old male and female Sost deficient (Sost) mice received LGK974 for 4 weeks and right hindlimbs were subjected to 20 N peak loading to assess mechanoadaptive interactions. µCT revealed significant reductions in vertebral trabecular number and lower cortical bone volume in loaded and non-loaded tibiae in male and female LGK974-treated Sost mice. Interestingly, the target engagement biomarker Axin2 was only significantly reduced in male vertebrae, which may indicate differences in male and female response to LGK974. This study also shows that PORCN inhibition may effectively limit characteristic HBM and skeletal overgrowth in sclerosteosis patients at sites with severe pathology.
骨硬化症是一种极为罕见的疾病，其特征为高骨量（HBM）和骨骼过度生长，可导致面部麻痹、听力丧失和颅内压升高，目前仅通过高风险手术进行治疗。骨硬化症由SOST突变和功能性硬化蛋白缺失引起，硬化蛋白是一种通过拮抗Wnt/β-连环蛋白信号传导来抑制骨生成的蛋白质。在此，我们使用体外和体内方法，探索另一种靶向刺猬蛋白（PORCN，Wnt特异性酰基转移酶）的强效Wnt抑制剂LGK974是否是一种有前景的骨硬化症治疗药物。体外试验表明，100 nmol/L LGK974显著降低成骨细胞碱性磷酸酶（ALP）活性/矿化，降低Wnt/成骨细胞标志物（Axin2、Runx2和Ocn）表达，并下调骨化和Wnt信号通路，而不影响破骨细胞数量/吸收。为了评估体内效应，6周龄的雄性和雌性Sost基因缺陷（Sost）小鼠接受LGK974治疗4周，右后肢承受20 N的峰值负荷以评估机械适应性相互作用。显微计算机断层扫描（µCT）显示，在接受LGK974治疗的雄性和雌性Sost小鼠中，加载和未加载的胫骨中椎骨小梁数量显著减少，皮质骨体积降低。有趣的是，靶点参与生物标志物Axin2仅在雄性椎骨中显著降低，这可能表明雄性和雌性对LGK974的反应存在差异。这项研究还表明，抑制PORCN可能有效限制骨硬化症患者严重病变部位的特征性高骨量和骨骼过度生长。
