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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 -
Trends in Molecular Medicine Aug 2014As the only cells definitively shown to degrade bone, osteoclasts are key mediators of skeletal diseases including osteoporosis. Bone-forming osteoblasts, and... (Review)
Review
As the only cells definitively shown to degrade bone, osteoclasts are key mediators of skeletal diseases including osteoporosis. Bone-forming osteoblasts, and hematopoietic and immune system cells, each influence osteoclast formation and function, but the reciprocal impact of osteoclasts on these cells is less well appreciated. We highlight here the functions that osteoclasts perform beyond bone resorption. First, we consider how osteoclast signals may contribute to bone formation by osteoblasts and to the pathology of bone lesions such as fibrous dysplasia and giant cell tumors. Second, we review the interaction of osteoclasts with the hematopoietic system, including the stem cell niche and adaptive immune cells. Connections between osteoclasts and other cells in the bone microenvironment are discussed within a clinically relevant framework.
Topics: Animals; Bone Remodeling; Bone Resorption; Bone and Bones; Fibrous Dysplasia of Bone; Giant Cell Tumor of Bone; Humans; Osteoclasts; Osteogenesis; Osteopetrosis; Osteoporosis
PubMed: 25008556
DOI: 10.1016/j.molmed.2014.06.001 -
Cells Jan 2022CLC proteins comprise Cl channels and anion/H antiporters involved in several fundamental physiological processes. ClC-7 is a lysosomal Cl/H antiporter that together... (Review)
Review
CLC proteins comprise Cl channels and anion/H antiporters involved in several fundamental physiological processes. ClC-7 is a lysosomal Cl/H antiporter that together with its beta subunit Ostm1 has a critical role in the ionic homeostasis of lysosomes and of the osteoclasts' resorption lacuna, although the specific underlying mechanism has so far remained elusive. Mutations in ClC-7 cause osteopetrosis, but also a form of lysosomal storage disease and neurodegeneration. Interestingly, both loss-of- and gain-of-function mutations of ClC-7 can be pathogenic, but the mechanistic implications of this finding are still unclear. This review will focus on the recent advances in our understanding of the biophysical properties of ClC-7 and of its role in human diseases with a focus on osteopetrosis and neurodegeneration.
Topics: Antiporters; Bone Resorption; Chloride Channels; Humans; Lysosomal Storage Diseases; Lysosomes; Osteopetrosis
PubMed: 35159175
DOI: 10.3390/cells11030366 -
Genes Oct 2022Osteopetrosis (from the Greek "osteo": bone; "petrosis": stone) is a clinically and genetically heterogeneous group of rare diseases of the skeleton, sharing the same... (Review)
Review
Osteopetrosis (from the Greek "osteo": bone; "petrosis": stone) is a clinically and genetically heterogeneous group of rare diseases of the skeleton, sharing the same main characteristic of an abnormally increased bone density. Dense bones in radiological studies are considered the hallmark of these diseases, and the reason for the common term used: "Marble bone disease". Interestingly, a radiologist, Dr. Albers-Schonberg, described this disease for the first time in Germany in 1904. Indeed, radiology has a key role in the clinical diagnosis of osteopetrosis and is fundamental in assessing the disease severity and complications, as well as in follow-up controls and the evaluation of the response to treatment. Osteopetrosis includes a broad spectrum of genetic mutations with very different clinical symptoms, age onset, and prognosis (from mild to severe). This diversity translates into different imaging patterns related to specific mutations, and different disease severity. The main recognized types of osteopetrosis are the infantile malignant forms with autosomal recessive transmission (ARO-including the rarer X-linked recessive form); the intermediate autosomal recessive form (IAO); and the autosomal dominant ones ADO, type I, and type II, the latter being called 'Albers-Schonberg' disease. Imaging features may change among those distinct types with different patterns, severities, skeletal segment involvement, and speeds of progression. There are several classical and well-recognized radiological features related to osteopetrosis: increased bone density (all types with different degrees of severity assuming a 'Marble Bone Appearance' especially in the ARO type), different metaphyseal alterations/enlargement including the so-called 'Erlenmeyer flask deformity' (particularly of femoral bones, more frequent in ADO type 2, and less frequent in ARO and IAO), 'bone in bone' appearance (more frequent in ADO type 2, less frequent in ARO and IAO), and 'rugger-jersey spine' appearance (typical of ADO type 2). After conducting an overview of the epidemiological and clinical characteristic of the disease, this review article aims at summarizing the main radiological features found in different forms of osteopetrosis together with their inheritance pattern.
Topics: Humans; Osteopetrosis; Genes, Dominant; Inheritance Patterns; Radiology; Calcium Carbonate
PubMed: 36360203
DOI: 10.3390/genes13111965 -
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 -
Journal of Ayub Medical College,... 2017Two main forms of osteopetrosis are recognized, a severe autosomal recessive form (MIM 259700) with an incidence of approximately 1 in 250,000 births and a mild...
Two main forms of osteopetrosis are recognized, a severe autosomal recessive form (MIM 259700) with an incidence of approximately 1 in 250,000 births and a mild autosomal dominant form (MIM166600) with an incidence of 1 in 20,000 births. Intrinsic disturbances of osteoclastic function due to mutations in genes encoding osteoclast-specific subunits of the vacuolar proton pump (TCIRG1, CLCN7) are found in most patients with recessive form. Mutations of CLCN7 are observed in dominant form of osteopetrosis .The recessive form of ostreopetrosis, i.e., malignant infantile osteopetrosis (MIOP) presents early in life with extreme sclerosis of the skeleton and reduction of marrow space. Signs/symptoms of MIOP appear as early as neonatal age. As there is defect in bone marrow children present with deficiency of red blood cells, white blood cells and platelets. There is extramedullary haemopoiesis, cranial nerve compressions and severe growth failure. The condition also presents with early and late onset neonatal sepsis and is often lethal in the first decade of life due to secondary infections. Treatment is mainly supportive. The only curative treatment is stem cell transplantation. This is a case report of a new-born who was admitted in nursery of Ayub Teaching Hospital initially with complains of neonatal jaundice and sepsis , and a second time with lower respiratory tract infection. Death was eventually due to sepsis. Workup led to diagnosis of Malignant infantile osteopetrosis.
Topics: Biopsy; Bone Marrow; Chloride Channels; DNA Mutational Analysis; DNA, Neoplasm; Fatal Outcome; Humans; Infant, Newborn; Male; Mutation; Osteopetrosis; Radiography; Vacuolar Proton-Translocating ATPases
PubMed: 28718264
DOI: No ID Found -
BioFactors (Oxford, England) 2011Calcium transport and calcium signaling are of basic importance in bone cells. Bone is the major store of calcium and a key regulatory organ for calcium homeostasis.... (Review)
Review
Calcium transport and calcium signaling are of basic importance in bone cells. Bone is the major store of calcium and a key regulatory organ for calcium homeostasis. Bone, in major part, responds to calcium-dependent signals from the parathyroids and via vitamin D metabolites, although bone retains direct response to extracellular calcium if parathyroid regulation is lost. Improved understanding of calcium transporters and calcium-regulated cellular processes has resulted from analysis of genetic defects, including several defects with low or high bone mass. Osteoblasts deposit calcium by mechanisms including phosphate and calcium transport with alkalinization to absorb acid created by mineral deposition; cartilage calcium mineralization occurs by passive diffusion and phosphate production. Calcium mobilization by osteoclasts is mediated by acid secretion. Both bone forming and bone resorbing cells use calcium signals as regulators of differentiation and activity. This has been studied in more detail in osteoclasts, where both osteoclast differentiation and motility are regulated by calcium.
Topics: Animals; Bone Diseases; Calcium; Chondrocalcinosis; Humans; Hypercalcemia; Models, Biological; Osteonecrosis; Osteopetrosis; Osteoporosis
PubMed: 21674636
DOI: 10.1002/biof.143 -
Bone Sep 2017Osteopetroses are a heterogeneous group of rare genetic bone diseases sharing the common hallmarks of reduced osteoclast activity, increased bone mass and high bone... (Review)
Review
Osteopetroses are a heterogeneous group of rare genetic bone diseases sharing the common hallmarks of reduced osteoclast activity, increased bone mass and high bone fragility. Osteoclasts are bone resorbing cells that contribute to bone growth and renewal through the erosion of the mineralized matrix. Alongside the bone forming activity by osteoblasts, osteoclasts allow the skeleton to grow harmonically and maintain a healthy balance between bone resorption and formation. Osteoclast impairment in osteopetroses prevents bone renewal and deteriorates bone quality, causing atraumatic fractures. Osteopetroses vary in severity and are caused by mutations in a variety of genes involved in bone resorption or in osteoclastogenesis. Frequent signs and symptoms include osteosclerosis, deformity, dwarfism and narrowing of the bony canals, including the nerve foramina, leading to hematological and neural failures. The disease is autosomal, with only one extremely rare form associated so far to the X-chromosome, and can have either recessive or dominant inheritance. Recessive ostepetroses are generally lethal in infancy or childhood, with a few milder forms clinically denominated intermediate osteopetroses. Dominant osteopetrosis is so far associated only with mutations in the CLCN7 gene and, although described as a benign form, it can be severely debilitating, although not at the same level as recessive forms, and can rarely result in reduced life expectancy. Severe osteopetroses due to osteoclast autonomous defects can be treated by Hematopoietic Stem Cell Transplant (HSCT), but those due to deficiency of the pro-osteoclastogenic cytokine, RANKL, are not suitable for this procedure. Likewise, it is unclear as to whether HSCT, which has high intrinsic risks, results in clinical improvement in autosomal dominant osteopetrosis. Therefore, there is an unmet medical need to identify new therapies and studies are currently in progress to test gene and cell therapies, small interfering RNA approach and novel pharmacologic treatments.
Topics: Animals; Genetic Association Studies; Humans; Osteopetrosis
PubMed: 28167345
DOI: 10.1016/j.bone.2017.02.002 -
Acta Reumatologica Portuguesa 2009
Topics: Adult; Humans; Male; Osteopetrosis; Radiography
PubMed: 19365311
DOI: No ID Found -
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