Extra-skeletal manifestations in mice affected by Clcn7-dependent autosomal dominant osteopetrosis type 2 clinical and therapeutic implications

作     者：Antonio Maurizi Mattia Capulli Annabel Curle Rajvi Patel Argia Ucci Juliana Alves Cotes Harriet Oxford Shireen R. Lamandé John F. Bateman Nadia Rucci Anna Teti 

作者机构：Department of Biotechnological and Applied Clinical SciencesUniversity of L’AquilaL’AquilaItaly Murdoch Children’s Research Institute and University of MelbourneMelbourneAustralia 

出 版 物：《Bone Research》 (骨研究（英文版）)

年 卷 期：2019年第7卷第2期

页      面：195-209页

核心收录：

学科分类：10[医学] 

基　　金：supported by the Fondazione Telethon Grants GGP09018 and GGP14014 the European Union funded project SYBIL—FP7-HEALTH-2013-INNOVATION—602300 the Progetti di Rilevante Interesse Nazionale(PRIN)grant 2015F3JHMB to A.T.A.M A.U.were recipients of Marie Curie fellowships from the European Union funded project RUBICON—H2020-MSCA-RISE-2015_690850 to A.T 

主　　题：Extra-skeletal manifestations dominant osteopetrosis implications 

摘      要：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 *** 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 *** hallmark of the extra-skeletal alterations is a consistent perivascular fibrosis,associated with high numbers of macrophages and lymphoid *** 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 ***2 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 ***-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 ***,an experimental siRNA therapy,previously proven to counteract the bone phenotype,also improves the extra-skeletal *** 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.