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Orphanet Journal of Rare Diseases Feb 2009Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density... (Review)
Review
Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy.
Topics: Adult; Bone Marrow Diseases; Child, Preschool; Fractures, Spontaneous; Genes, Dominant; Genes, Recessive; Humans; Infant, Newborn; Osteoclasts; Osteopetrosis; Prevalence
PubMed: 19232111
DOI: 10.1186/1750-1172-4-5 -
Bone May 2023Autosomal dominant osteopetrosis (ADO) is the most common form of osteopetrosis. ADO is characterized by generalized osteosclerosis along with characteristic... (Review)
Review
Autosomal dominant osteopetrosis (ADO) is the most common form of osteopetrosis. ADO is characterized by generalized osteosclerosis along with characteristic radiographic features such as a "bone-in-bone" appearance of long bones and sclerosis of the superior and inferior vertebral body endplates. Generalized osteosclerosis in ADO typically results from abnormalities in osteoclast function, due most commonly to mutations in the chloride channel 7 (CLCN7) gene. A variety of debilitating complications can occur over time due to bone fragility, impingement of cranial nerves, encroachment of osteopetrotic bone in the marrow space, and poor bone vascularity. There is a wide spectrum of disease phenotype, even within the same family. Currently, there is no disease specific treatment for ADO, so clinical care focuses on monitoring for disease complications and symptomatic treatment. This review describes the history of ADO, the wide disease phenotype, and potential new therapies.
Topics: Humans; Osteopetrosis; Mutation; Osteoclasts; Chloride Channels; Genes, Dominant
PubMed: 36863500
DOI: 10.1016/j.bone.2023.116723 -
Nature Apr 2019Osteoclasts are multinucleated giant cells that resorb bone, ensuring development and continuous remodelling of the skeleton and the bone marrow haematopoietic niche....
Osteoclasts are multinucleated giant cells that resorb bone, ensuring development and continuous remodelling of the skeleton and the bone marrow haematopoietic niche. Defective osteoclast activity leads to osteopetrosis and bone marrow failure, whereas excess activity can contribute to bone loss and osteoporosis. Osteopetrosis can be partially treated by bone marrow transplantation in humans and mice, consistent with a haematopoietic origin of osteoclasts and studies that suggest that they develop by fusion of monocytic precursors derived from haematopoietic stem cells in the presence of CSF1 and RANK ligand. However, the developmental origin and lifespan of osteoclasts, and the mechanisms that ensure maintenance of osteoclast function throughout life in vivo remain largely unexplored. Here we report that osteoclasts that colonize fetal ossification centres originate from embryonic erythro-myeloid progenitors. These erythro-myeloid progenitor-derived osteoclasts are required for normal bone development and tooth eruption. Yet, timely transfusion of haematopoietic-stem-cell-derived monocytic cells in newborn mice is sufficient to rescue bone development in early-onset autosomal recessive osteopetrosis. We also found that the postnatal maintenance of osteoclasts, bone mass and the bone marrow cavity involve iterative fusion of circulating blood monocytic cells with long-lived osteoclast syncytia. As a consequence, parabiosis or transfusion of monocytic cells results in long-term gene transfer in osteoclasts in the absence of haematopoietic-stem-cell chimerism, and can rescue an adult-onset osteopetrotic phenotype caused by cathepsin K deficiency. In sum, our results identify the developmental origin of osteoclasts and a mechanism that controls their maintenance in bones after birth. These data suggest strategies to rescue osteoclast deficiency in osteopetrosis and to modulate osteoclast activity in vivo.
Topics: Animals; Animals, Newborn; Bone Development; Female; Genes, Recessive; Hematopoietic Stem Cells; Male; Mice; Osteoclasts; Osteopetrosis; Tooth Eruption
PubMed: 30971820
DOI: 10.1038/s41586-019-1105-7 -
Medicina 2023
Topics: Humans; Melorheostosis; Diagnosis, Differential
PubMed: 37870352
DOI: No ID Found -
Nature Communications Sep 2022Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including...
Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1β serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1β overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1β in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1β in JAK2-V617F mutant mice by anti-IL-1β antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1β with anti-IL-1β antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.
Topics: Animals; Interleukin-1beta; Janus Kinase 2; Mice; Mice, Knockout; Myeloproliferative Disorders; Neoplasms; Nitriles; Osteosclerosis; Primary Myelofibrosis; Pyrazoles; Pyrimidines
PubMed: 36100613
DOI: 10.1038/s41467-022-32927-4 -
Disease Models & Mechanisms May 2021Autosomal recessive osteopetrosis (ARO) is a severe inherited bone disease characterized by defective osteoclast resorption or differentiation. Clinical manifestations... (Review)
Review
Autosomal recessive osteopetrosis (ARO) is a severe inherited bone disease characterized by defective osteoclast resorption or differentiation. Clinical manifestations include dense and brittle bones, anemia and progressive nerve compression, which hamper the quality of patients' lives and cause death in the first 10 years of age. This Review describes the pathogenesis of ARO and highlights the strengths and weaknesses of the current standard of care, namely hematopoietic stem cell transplantation (HSCT). Despite an improvement in the overall survival and outcomes of HSCT, transplant-related morbidity and the pre-existence of neurological symptoms significantly limit the success of HSCT, while the availability of human leukocyte antigen (HLA)-matched donors still remains an open issue. Novel therapeutic approaches are needed for ARO patients, especially for those that cannot benefit from HSCT. Here, we review preclinical and proof-of-concept studies, such as gene therapy, systematic administration of deficient protein, in utero HSCT and gene editing.
Topics: Consensus; Gene Expression Regulation; Genes, Recessive; Humans; Osteoclasts; Osteopetrosis; Practice Guidelines as Topic
PubMed: 33970241
DOI: 10.1242/dmm.048940 -
Biomolecules Jan 2021Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hematopoietic stem-cell-derived clonal proliferation, leading to bone marrow (BM) fibrosis.... (Review)
Review
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hematopoietic stem-cell-derived clonal proliferation, leading to bone marrow (BM) fibrosis. Hematopoiesis alterations are closely associated with modifications of the BM microenvironment, characterized by defective interactions between vascular and endosteal niches. As such, neoangiogenesis, megakaryocytes hyperplasia and extensive bone marrow fibrosis, followed by osteosclerosis and bone damage, are the most relevant consequences of PMF. Moreover, bone tissue deposition, together with progressive fibrosis, represents crucial mechanisms of disabilities in patients. Although the underlying mechanisms of bone damage observed in PMF are still unclear, the involvement of cytokines, growth factors and bone marrow microenvironment resident cells have been linked to disease progression. Herein, we focused on the role of megakaryocytes and their alterations, associated with cytokines and chemokines release, in modulating functions of most of the bone marrow cell populations and in creating a complex network where impaired signaling strongly contributes to progression and disabilities.
Topics: Animals; Bone Marrow; Disease Progression; Humans; Monocytes; Osteosclerosis; Primary Myelofibrosis; Signal Transduction
PubMed: 33477816
DOI: 10.3390/biom11010122 -
The Korean Journal of Internal Medicine Sep 2019
Topics: Adult; Female; Genetic Predisposition to Disease; Heredity; Humans; Medical History Taking; Osteopetrosis; Pedigree; Phenotype; Predictive Value of Tests; Radiography, Thoracic; Tomography, X-Ray Computed
PubMed: 29761793
DOI: 10.3904/kjim.2018.026 -
American Family Physician Mar 1998Osteopetrosis is a rare hereditary bone disorder that presents in one of three forms: osteopetrosis tarda, osteopetrosis congenita and "marble bone" disease.... (Review)
Review
Osteopetrosis is a rare hereditary bone disorder that presents in one of three forms: osteopetrosis tarda, osteopetrosis congenita and "marble bone" disease. Osteopetrosis tarda, the benign form, presents in adulthood, while the two more malignant variants, osteopetrosis congenita and marble bone disease, present in infancy and childhood, respectively. In all three forms, the main features are pathologic alteration of osteoclastic bone resorption and thickening of cortical and lamellar bones. Osteopetrosis tarda is usually discovered accidentally on routine radiographs and is often asymptomatic; however, patients may present because of related degenerative joint disease. Osteopetrosis congenita results in bone marrow failure and is almost always fatal. Marble bone disease causes short stature, cerebral calcification and mental retardation. Bone marrow transplant is the only chance for survival in patients with osteopetrosis congenita.
Topics: Age of Onset; Diagnosis, Differential; Humans; Male; Middle Aged; Osteopetrosis; Prognosis
PubMed: 9531912
DOI: No ID Found -
Revista Chilena de Pediatria Aug 2019Malignant Infantile Osteopetrosis (MIOP) is a rare and severe genetic disorder due to abnormal osteoclast activity.
INTRODUCTION
Malignant Infantile Osteopetrosis (MIOP) is a rare and severe genetic disorder due to abnormal osteoclast activity.
OBJECTIVE
To report an infant who presented Malignant Infantile Osteopetrosis, reviewing the most relevant diagnostic and therapeutic aspects.
CLINICAL CASE
A ten- month-old male infant with diagnosis of MIOP confirmed after presenting thrombocytopenia and visceromegaly. He was the first child of non-consanguineous parents, and among the findings, he presented severe hepatosplenomegaly, thrombocytopenia, and anemia; visual and hearing impair ment, and repeated infections. The diagnosis was confirmed by genetic study, which identified two heterozygous mutations in the TCIRG1 gene. Hematopoietic stem cells were transplanted without hematological recovery. The patient died due to occlusive venous disease.
DISCUSSION
MIOP is a rare, severe, and early-onset disease, with a high rate of suspicion necessary in the presence of hepa- tosplenomegaly and bone marrow failure. Early diagnosis and hematopoietic stem cells transplanta tion are the only potentially therapeutic interventions of this lethal entity.
Topics: Fatal Outcome; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Mutation; Osteopetrosis; Vacuolar Proton-Translocating ATPases
PubMed: 31859718
DOI: 10.32641/rchped.v90i4.987