Autosomal dominant osteopetrosis type 2 (ADO2) is a high-density brittle bone disease characterized by bone pain, multiple fractures and skeletal-related events, including nerve compression syndrome and hematological failure. We demonstrated that in mice carrying the heterozygous Clcn7^G213R mutation, whose human mutant homolog CLCN7^G215R affects patients, the clinical impacts of ADO2 extend beyond the skeleton, affecting several other organs. The hallmark of the extra-skeletal alterations is a consistent perivascular fibrosis, associated with high numbers of macrophages and lymphoid infiltrates. Fragmented clinical information in a small cohort of patients confirms extra-skeletal alterations consistent with a systemic disease, in line with the observation that the CLCN7 gene is expressed in many organs. ADO2 mice also show anxiety and depression and their brains exhibit not only perivascular fibrosis but also β-amyloid accumulation and astrogliosis, suggesting the involvement of the nervous system in the pathogenesis of the ADO2 extra-skeletal alterations. Extra-skeletal organs share a similar cellular pathology, confirmed also in vitro in bone marrow mononuclear cells and osteoclasts, characterized by an impairment of the exit pathway of the Clcn7 protein product, ClC7, through the Golgi, with consequent reduced ClC7 expression in late endosomes and lysosomes, associated with high vesicular pH and accumulation of autophagosome markers. Finally, an experimental siRNA therapy, previously proven to counteract the bone phenotype, also improves the extra-skeletal alterations. These results could have important clinical implications, supporting the notion that a systematic evaluation of ADO2 patients for extra-skeletal symptoms could help improve their diagnosis, clinical management, and therapeutic options.

常染色体显性遗传骨质疏松症2型（ADO2）是一种高密度脆性骨病，其特征是骨痛，多处骨折和与骨骼有关的事件，包括神经压迫综合征和血液学衰竭。我们证明了在携带杂合子Clcn7 ^G213R突变的小鼠中，其人类突变体同系物CLCN7 ^G215R在影响患者时，ADO2的临床影响超出了骨骼，影响了其他几个器官。骨骼外改变的标志是持续的血管周围纤维化，伴有大量的巨噬细胞和淋巴样浸润。一小部分患者的临床信息零散，证实与系统性疾病一致的骨骼外改变，与观察到的CLCN7一致基因在许多器官中表达。ADO2小鼠还表现出焦虑和抑郁，其大脑不仅表现出血管周围纤维化，还表现出β-淀粉样蛋白积累和星形胶质细胞增生，表明神经系统参与了ADO2骨骼外变化的发病机制。骨骼外器官具有相似的细胞病理学，也已在体外在骨髓单个核细胞和破骨细胞中得到证实，其特征是Clcn7出口途径受损蛋白产物ClC7，通过高尔基体，因此在晚期内体和溶酶体中ClC7表达降低，与高囊泡pH和自噬标记物的积累有关。最后，先前被证明可以抵消骨表型的实验性siRNA治疗也可以改善骨骼外变化。这些结果可能具有重要的临床意义，支持以下观点：对ADO2患者的骨骼外症状进行系统评估可以帮助改善他们的诊断，临床管理和治疗选择。