Osteopetrosis: genetics, treatment and new insights into osteoclast function

Cristina Sobacchi, Ansgar Schulz, Fraser P. Coxon, Anna Villa, Miep H. Helfrich

Research output: Contribution to journalArticle

201 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)522-536
Number of pages15
JournalNature Reviews Endocrinology
Volume9
Early online date23 Jul 2013
DOIs
Publication statusPublished - Sep 2013

Fingerprint

Osteopetrosis
Osteoclasts
Therapeutics
Bone and Bones
Mutation
Inborn Genetic Diseases
Hematopoietic Stem Cell Transplantation
Hypercalcemia
Diagnostic Errors
Cartilage
Stem Cells
Parturition
Guidelines

Keywords

  • Animals
  • Humans
  • Osteopetrosis
  • RANK Ligand
  • Signal Transduction

Cite this

Osteopetrosis : genetics, treatment and new insights into osteoclast function. / Sobacchi, Cristina; Schulz, Ansgar; Coxon, Fraser P.; Villa, Anna; Helfrich, Miep H.

In: Nature Reviews Endocrinology , Vol. 9, 09.2013, p. 522-536.

Research output: Contribution to journalArticle

Sobacchi, Cristina ; Schulz, Ansgar ; Coxon, Fraser P. ; Villa, Anna ; Helfrich, Miep H. / Osteopetrosis : genetics, treatment and new insights into osteoclast function. In: Nature Reviews Endocrinology . 2013 ; Vol. 9. pp. 522-536.
@article{25ba01f1ea8a4f6db98a343eb1ff9210,
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.",
keywords = "Animals, Humans, Osteopetrosis, RANK Ligand, Signal Transduction",
author = "Cristina Sobacchi and Ansgar Schulz and Coxon, {Fraser P.} and Anna Villa and Helfrich, {Miep H.}",
note = "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.",
year = "2013",
month = "9",
doi = "10.1038/nrendo.2013.137",
language = "English",
volume = "9",
pages = "522--536",
journal = "Nature Reviews Endocrinology",
issn = "1759-5029",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Osteopetrosis

T2 - genetics, treatment and new insights into osteoclast function

AU - Sobacchi, Cristina

AU - Schulz, Ansgar

AU - Coxon, Fraser P.

AU - Villa, Anna

AU - Helfrich, Miep H.

N1 - 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.

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

KW - Animals

KW - Humans

KW - Osteopetrosis

KW - RANK Ligand

KW - Signal Transduction

U2 - 10.1038/nrendo.2013.137

DO - 10.1038/nrendo.2013.137

M3 - Article

C2 - 23877423

VL - 9

SP - 522

EP - 536

JO - Nature Reviews Endocrinology

JF - Nature Reviews Endocrinology

SN - 1759-5029

ER -