Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gα_s variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191

纤维发育不良 (FD) 是一种罕见的致残性骨骼疾病，目前尚无成熟的治疗方法。越来越多的证据支持抑制核 kappa-B 配体 (RANKL) 的破骨细胞因子受体激活剂 (RANKL) 作为一种潜在的治疗策略。在本研究中，我们通过在狄诺塞麦 (NCT03571191) 2 期临床试验以及小鼠体内和体外试验中评估人 FD 组织治疗前和治疗后，研究了 FD 组织中 RANKL 抑制的机制及其可能对骨祖细胞的间接影响。体内临床前模型。对人和小鼠组织的组织学分析表明，RANKL 抑制后，FD 病变中成骨成熟增加、细胞结构减少以及致病性 Gα _s变异表达减少。人类和小鼠组织的 RNA 测序支持了这些发现。在离体病变模型中进一步评估了破骨细胞和突变骨祖细胞之间的相互作用，这表明异常FD骨祖细胞的增殖依赖于破骨细胞。这项研究的结果表明，除了预期的抗破骨作用外，狄诺塞麦还可以通过减少 FD 细胞增殖和增加成骨成熟来降低 FD 病变活性，从而增加病变内的骨形成。这些发现强调了破骨细胞和前成骨细胞/成骨细胞之间的细胞串扰作为 FD 病理学驱动因素的未被认识到的作用，并证明了狄诺塞麦在骨病治疗中的一种新作用机制。

试验注册：ClinicalTrials.gov NCT03571191