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.

Osteopetrosis: genetics, treatment and new insights into osteoclast function

Mechanisms of disease osteopetrosis

Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.

Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL

Bone and cartilage and their disorders are addressed under the following headings: functions of bone; normal and abnormal bone remodeling; osteopetrosis and osteoporosis; epithelial-mesenchymal interaction, condensation and differentiation; osteoblasts, markers of bone formation, osteoclasts, components of bone, and pathology of bone; chondroblasts, markers of cartilage formation, secondary cartilage, components of cartilage, and pathology of cartilage; intramembranous and endochondral bone formation; RUNX genes and cleidocranial dysplasia (CCD); osterix; histone deacetylase 4 and Runx2; Ligand to receptor activator of NFkappaB (RANKL), RANK, osteoprotegerin, and osteoimmunology; WNT signaling, LRP5 mutations, and beta-catenin; the role of leptin in bone remodeling; collagens, collagenopathies, and osteogenesis imperfecta; FGFs/FGFRs, FGFR3 skeletal dysplasias, craniosynostosis, and other disorders; short limb chondrodysplasias; molecular control of the growth plate in endochondral bone formation and genetic disorders of IHH and PTHR1; ANKH, craniometaphyseal dysplasia, and chondrocalcinosis; transforming growth factor beta, Camurati-Engelmann disease (CED), and Marfan syndrome, types I and II; an ACVR1 mutation and fibrodysplasia ossificans progressiva; MSX1 and MSX2: biology, mutations, and associated disorders; G protein, activation of adenylyl cyclase, GNAS1 mutations, McCune-Albright syndrome, fibrous dysplasia, and Albright hereditary osteodystrophy; FLNA and associated disorders; and morphological development of teeth and their genetic mutations

The new bone biology: pathologic, molecular, and clinical correlates.

Bone is a dynamic organ constantly remodeled to support calcium homeostasis and structural needs. The osteoclast is the cell responsible for removing both the organic and inorganic components of bone. It is derived from hematopoietic progenitors in the macrophage lineage and differentiates in response to the tumor necrosis factor family cytokine receptor activator of NFκB ligand. αvβ3 integrin mediates cell adhesion necessary for polarization and formation of an isolated, acidified resorptive microenvironment. Defects in osteoclast function, whether genetic or iatrogenic, may increase bone mass but lead to poor bone quality and a high fracture risk. Pathological stimulation of osteoclast formation and resorption occurs in postmenopausal osteoporosis, inflammatory arthritis, and metastasis of tumors to bone. In these diseases, osteoclast activity causes bone loss that leads to pain, deformity, and fracture. Thus, osteoclasts are critical for normal bone function, but their activity must be controlled.

The Osteoclast: Friend or Foe?

Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogenous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for similar to 50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition. (Less)

https://www.zora.uzh.ch/id/eprint/154650/1/ZORA_NL_154650.pdf

Virginia Gulino

Papers

The mutational spectrum of human malignant autosomal recessive osteopetrosis