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Medecine Sciences : M/S Jan 2004The osteoclast is the main effector of bone resorption. Failure in osteoclast differentiation or function leads to osteopetrosis, a bone disease characterized by an... (Review)
Review
The osteoclast is the main effector of bone resorption. Failure in osteoclast differentiation or function leads to osteopetrosis, a bone disease characterized by an impaired bone resorption. Analysis of mouse models developing osteopetrosis as a consequence of naturally occurring mutations or gene knockouts allowed to establish the osteoclast differentiation pathway. Among these models, the oc/oc, the gl/gl and the Clcn7(-/-) mice present a phenotype similar to the one displayed by patients with infantile malignant osteopetrosis, the most severe form of osteopetrosis in human. Analysis of these models led to the identification of different mutations in the corresponding human genes TCIRG1, GL and CLCN7, in osteopetrotic patients. Mutations in the TCIRG1 gene seem the most frequent cause of malignant osteopetrosis and mutations in the CLCN7 gene seem the most frequent cause of type II osteopetrosis. Therefore, these three mouse models appear to be particularly well suited for the study of the osteoclast function in order to provide new insights in the therapy of osteopetrosis.
Topics: Animals; Cell Differentiation; Disease Models, Animal; Humans; Mice; Osteoclasts; Osteopetrosis
PubMed: 14770365
DOI: 10.1051/medsci/200420161 -
Nature Reviews. Endocrinology Sep 2013Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal... (Review)
Review
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.
Topics: Animals; Humans; Osteopetrosis; RANK Ligand; Signal Transduction
PubMed: 23877423
DOI: 10.1038/nrendo.2013.137 -
European Journal of Medical Genetics Jun 2024Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone... (Review)
Review
Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.
Topics: Osteopetrosis; Humans; Osteoclasts; Adult; Chloride Channels; Mutation
PubMed: 38593953
DOI: 10.1016/j.ejmg.2024.104936 -
Seminars in Nephrology Mar 1992
Review
Topics: Bone Marrow Transplantation; Bone and Bones; Chromosome Aberrations; Chromosome Disorders; Combined Modality Therapy; Genes, Dominant; Genes, Recessive; Humans; Osteopetrosis; Radiography
PubMed: 1561496
DOI: No ID Found -
Tropical Doctor Jul 2019Osteopetrosis is a rare congenital disease presenting with recurrent fractures, hematopoietic insufficiency and hepatosplenomegaly. Though osteomyelitis is a known...
Osteopetrosis is a rare congenital disease presenting with recurrent fractures, hematopoietic insufficiency and hepatosplenomegaly. Though osteomyelitis is a known complication in osteopetrosis, osteopetrosis presenting as osteomyelitis is rare. Management consists of multidisciplinary approach for complications and bone marrow transplant for the infantile form of disease.
Topics: Child; Humans; Male; Osteomyelitis; Osteopetrosis; Radiography
PubMed: 30895884
DOI: 10.1177/0049475519833548 -
Archives of Disease in Childhood Jun 1971The clinical histories of nine children with osteopetrosis are reported. Two of them had the malignant infantile variety of the disease: one died within 3 months of...
The clinical histories of nine children with osteopetrosis are reported. Two of them had the malignant infantile variety of the disease: one died within 3 months of birth and the other has survived 20 months on a regimen of a low calcium intake, cellulose phosphate, and steroids. The beneficial effect of a low calcium intake, in early infancy, is supported by the clinical course in the infant with the malignant variety and in another child with the more benign form of the disease. No calcium balance studies were performed. This study suggests that the active measures outlined may favourably influence the haematological and osteosclerotic course of the disease, pending further knowledge of its aetiological basis, and more specific therapy.
Topics: Calcium, Dietary; Cellulose; Child, Preschool; Diet Therapy; Female; Humans; Infant; Infant, Newborn; Male; Osteopetrosis; Phosphates; Prednisone; Radiography
PubMed: 5090659
DOI: 10.1136/adc.46.247.257 -
Bone Oct 2022Autosomal recessive osteopetroses (ARO) are rare genetic skeletal disorders of high clinical and molecular heterogeneity with an estimated frequency of 1:250,000...
Autosomal recessive osteopetroses (ARO) are rare genetic skeletal disorders of high clinical and molecular heterogeneity with an estimated frequency of 1:250,000 worldwide. The manifestations are diverse and although individually rare, the various forms contribute to the prevalence of a significant number of affected individuals with considerable morbidity and mortality. Among the ARO classification, the most severe form is the autosomal recessive-5 (OPTB5) osteopetrosis (OMIM 259720) that results from homozygous mutation in the OSTM1 gene (607649). OSTM1 mutations account for approximately 5 % of instances of autosomal recessive osteopetrosis and lead to a highly debilitating form of the disease in infancy and death within the first few years of life (Sobacchi et al., 2013) [1].
Topics: Homozygote; Humans; Membrane Proteins; Mutation; Osteopetrosis; Ubiquitin-Protein Ligases
PubMed: 35902071
DOI: 10.1016/j.bone.2022.116505 -
Clinical Orthopaedics and Related... Sep 1978
Review
Topics: Animals; Bone Marrow Transplantation; Bone and Bones; Female; Humans; Infant; Mice; Osteopetrosis; Parabiosis; Rats; Thymus Gland; Transplantation, Homologous
PubMed: 361322
DOI: No ID Found -
Frontiers in Bioscience (Landmark... Jun 2023Osteopetrosis represents a rare genetic disease with a wide range of clinical and genetic heterogeneity, which results from osteoclast failure. Although up to 10 genes...
BACKGROUND
Osteopetrosis represents a rare genetic disease with a wide range of clinical and genetic heterogeneity, which results from osteoclast failure. Although up to 10 genes have been identified to be related with osteopetrosis, the pathogenesis of osteopetrosis remains foggy. Disease-specific induced pluripotent stem cells (iPSCs) and gene-corrected disease specific iPSCs provide a platform to generate attractive disease cell models and isogenic control cellular models respectively. The purpose of this study is to rescue the disease causative mutation in osteopetrosis specific induced pluripotent stem cells and provide isogenic control cellular models.
METHODS
Based on our previously established osteopetrosis-specific iPSCs (ADO2-iPSCs), we repaired the point mutation R286W of the gene in ADO2-iPSCs by the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mediated homologous recombination.
RESULTS
The obtained gene corrected ADO2-iPSCs (GC-ADO2-iPSCs) were characterized in terms of hESC-like morphology, a normal karyotype, expression of pluripotency markers, homozygous repaired sequence of gene, and the ability to differentiate into cells of three germ layers.
CONCLUSIONS
We successfully corrected the point mutation R286W of the gene in ADO2-iPSCs. This isogenic iPSC line is an ideal control cell model for deciphering the pathogenesis of osteopetrosis in future studies.
Topics: Humans; Induced Pluripotent Stem Cells; CRISPR-Cas Systems; Osteopetrosis; Mutation; Chloride Channels
PubMed: 37395026
DOI: 10.31083/j.fbl2806131 -
Neuropathology and Applied Neurobiology Apr 2003The osteopetroses are caused by reduced activity of osteoclasts which results in defective remodelling of bone and increased bone density. They range from a devastating... (Review)
Review
The osteopetroses are caused by reduced activity of osteoclasts which results in defective remodelling of bone and increased bone density. They range from a devastating neurometabolic disease, through severe malignant infantile osteopetrosis (OP) to two more benign conditions principally affecting adults [autosomal dominant OP (ADO I and II)]. In many patients the disease is caused by defects in either the proton pump [the a3 subunit of vacuolar-type H(+)-ATPase, encoded by the gene variously termed ATP6i or TCIRG1] or the ClC-7 chloride channel (ClCN7 gene). These pumps are responsible for acidifying the bone surface beneath the osteoclast. Although generally thought of as bone diseases, the most serious consequences of the osteopetroses are seen in the nervous system. Cranial nerves, blood vessels and the spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina. Most patients with OP have some degree of optic atrophy and many children with severe forms of autosomal recessive OP are rendered blind; optic decompression is frequently attempted to prevent the latter. Auditory, facial and trigeminal nerves may also be affected, and hydrocephalus can develop. Stenosis of both arterial supply (internal carotid and vertebral arteries) and venous drainage may occur. The least understood form of the disease is neuronopathic OP [OP and infantile neuroaxonal dystrophy, MIM (Mendelian inheritance in man) 600329] which causes rapid neurodegeneration and death within the first year. Although characterized by the finding of widespread axonal spheroids and accumulation of ceroid lipofuscin, the biochemical basis of this disease remains unknown. The neurological complications of this disease and other variants are presented in the context of the latest classification of the disease.
Topics: Animals; Blindness; Child; Cranial Nerve Diseases; Hematologic Diseases; Humans; Models, Animal; Nervous System Diseases; Optic Atrophy; Osteopetrosis; Psychomotor Disorders; Radiography
PubMed: 12662317
DOI: 10.1046/j.1365-2990.2003.00474.x