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.
Key Points
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Autosomal recessive osteopetrosis (ARO) is a genetically and phenotypically heterogeneous disease; most forms result from late endosomal trafficking defects that prevent osteoclast ruffled-border formation
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Early molecular diagnosis is essential to guide management decisions, and novel genetic tools should enable identification of causative mutations in all patients with ARO in the near future
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Haematopoietic stem cell transplantation (HSCT) can cure ARO if given in early life to patients with osteoclast-intrinsic disease without neurodegenerative complications
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New treatments that target RANKL/RANK signalling offer promise in ARO subtypes that currently cannot be cured by HSCT and to prevent hypercalcaemia after HSCT
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Study of osteopetrosis-causing mutations continues to identify essential genes for osteoclast function, to increase understanding of osteoclast biology and to reveal novel targets for therapeutic intervention
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Acknowledgements
The authors acknowledge grant support from the following sources: Ministero della Salute grants GR-2008-1134,625 to C. Sobacchi and RF-2009-1499,542 to A. Villa; Telethon Foundation grant GGP12178 to C. Sobacchi; Research Projects of National Interest (PRIN) Project grant 20122M7T8X_003 by the National Research Program-National Research Council (PNR-CNR) Aging Program 2012–2014 to A. Villa; Arthritis Research UK grants 17285 and 19379 to F. P. Coxon and M. H. Helfrich, respectively. The authors wish to thank: D. Mellis and J. Crockett (University of Aberdeen) for contributing Figure 4 panels a and d, and discussion regarding RANK and RANKL mutants; M. Hoenig (University Medical Centre, Ulm) for critical comments on the manuscript.
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Sobacchi, C., Schulz, A., Coxon, F. et al. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol 9, 522–536 (2013). https://doi.org/10.1038/nrendo.2013.137
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DOI: https://doi.org/10.1038/nrendo.2013.137
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