title: Osteopetrosis: genetics, treatment and new insights into osteoclast function.
abstract: Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal dominant forms exist, but this Review focuses on autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis. The genetic basis of this disease is now largely uncovered: mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function), whereas mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO. In osteoclast-rich ARO, impaired endosomal and lysosomal vesicle trafficking results in defective osteoclast ruffled-border formation and, hence, the inability to resorb bone and mineralized cartilage. ARO presents soon after birth and can be fatal if left untreated. However, the disease is heterogeneous in clinical presentation and often misdiagnosed. This article describes the genetics of ARO and discusses the diagnostic role of next-generation sequencing methods. The management of affected patients, including guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined. Finally, novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are also discussed.
authors.affiliation: Unit Of Support/Institute of Genetic and Biomedical Research, Milan Unit, National Research Council, Humanitas Clinical and Research Centre, Via Manzoni 113, 20089 Rozzano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sobacchi
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.forename: Fraser P
authors.initials: FP
authors.lastname: Coxon
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Miep H
authors.initials: MH
authors.lastname: Helfrich
mesh_terms: D000818:Animals; D006801:Humans; D010022:Osteopetrosis / Q000151:congenital / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D053245:RANK Ligand