Abstract
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 Clcn7G213R mutation, whose human mutant homolog CLCN7G215R 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.
Highlights
Autosomal dominant osteopetrosis type 2 (ADO2) is a rare disease known to affect the skeleton.[1]
We observed that Lysotracker® accumulated in the γadaptin-positive clathrin-coated vesicles of ADO2 cells, suggesting (Fig. 4l). These results suggest that the cellular pathology is similar in the skeletal and the extra-skeletal ADO2 phenotypes induced by the Clcn7G213R mutation
ADO2 has long been considered a benign form of osteopetrosis
Summary
Autosomal dominant osteopetrosis type 2 (ADO2) is a rare disease known to affect the skeleton.[1]. Dependent ADO2 pathophysiology until recently was the lack of a genuine ADO2 mouse model This was addressed in 2014 by the generation of an ADO2 mouse carrying the murine homolog (Clcn7G213R) of the most frequent human ADO2 mutation (CLCN7G215R).[7,16] Heterozygous Clcn7G213R mice manifest skeletal alterations like patients and have been extensively investigated for their bone phenotype[16] and to test therapies.[17,18,19] Review of the literature and our systematic evaluation of wild-type (WT) mice demonstrated that Clcn[7] is expressed in many organs and cell types beyond osteoclasts,[6,20,21] prompting us to hypothesize that.
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