Animal models of osteopetrosis: the impact of recent molecular developments on novel strategies for the therapeutic intervention
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Osteopetrosis
Pathogenesis
Osteoimmunology
Osteopetrosis
TCIRG1
Multinucleate
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Osteopetrosis
Bone remodeling
Bone remodeling period
Osteoimmunology
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The osteoclast is a bone-degrading polykaryon. Recent studies have clarified the differentiation of this cell and the biochemical mechanisms it uses to resorb bone. The osteoclast derives from a monocyte/macrophage precursor. Osteoclast formation requires permissive concentrations of M-CSF and is driven by contact with mesenchymal cells in bone that bear the TNF-family ligand RANKL. Osteoclast precursors express RANK, and the interaction between RANKL and RANK (which is inhibited by OPG) is the major determinant of osteoclast formation. Hormones, such as PTH/PTHrP, glucocorticoids and 1,25(OH)2D3, and humoral factors, including TNFalpha, interleukin-1, TGFss and prostaglandins, influence osteoclast formation by altering expression of these molecular factors. TNFalpha, IL-6 and IL-11 have also been shown to promote osteoclast formation by RANKL-independent processes. RANKL-dependent/independent osteoclast formation is likely to play an important role in conditions where there is pathological bone resorption such as inflammatory arthritis and malignant bone resorption. Osteoclast functional defects cause sclerotic bone disorders, many of which have recently been identified as specific genetic defects. Osteoclasts express specialized proteins including a vacuolar-type H+-ATPase that drives HCl secretion for dissolution of bone mineral. One v-ATPase component, the 116 kD V0 subunit, has several isoforms. Only one isoform, TCIRG1, is up-regulated in osteoclasts. Defects in TCIRG1 are common causes of osteopetrosis. HCl secretion is dependent on chloride channels; a chloride channel homologue, CLCN7, is another common defect in osteopetrosis. Humans who are deficient in carbonic anhydrase II or who have defects in phagocytosis also have variable defects in bone remodelling. Organic bone matrix is degraded by thiol proteinases, principally cathepsin K, and abnormalities in cathepsin K cause another sclerotic bone disorder, pycnodysostosis. Thus, bone turnover in normal subjects depends on relative expression of key cytokines, and defects in osteoclastic turnover usually reflect defects in specific ion transporters or enzymes that play essential roles in bone degradation.
RANK Ligand
Osteopetrosis
Osteoimmunology
Bone remodeling
Cathepsin K
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Osteoclasts, which are responsible for bone resorption, are rare cells with only 2-3 cells seen per 1mm3 of bone. However, the loss of function in osteoclasts, problems with their differentiation and decrease in their number lead to bone osteosclerosis/osteopetrosis. On the other hand, an increase in their number or function induces bone osteoporosis, indicating that osteoclasts play a pivotal role in bone homeostasis. It has been demonstrated that bone destruction and hypercalcemia induced by metastatic tumors are carried out by osteoclasts activated by the tumor cells, and the inhibition of osteoclast formation prevents the bone destruction and even bone metastasis. Abnormal osteoclast function is closely related to various diseases. Furthermore, osteoclasts are indispensable in forming bone marrow to produce blood cells, and the absence of osteoclasts causes osteopetrosis, resulting in extramedullary hematopoiesis. Although the physiological roles of osteoclasts are well described, the mechanisms of their differentiation remain to be elucidated. Recently, RANK (receptor activator of nuclear factor kappaB) and its ligand (RANKL) have been identified and their essential roles in osteoclastogenesis have been demonstrated, which has provided new insights into the osteoclast differentiation pathway. We have established an in vitro osteoclast culture system by isolating osteoclast precursor cells and culturing them in the presence of macrophage colony stimulating factor (M-CSF) and soluble RANKL. This system has enabled us to analyze the regulation mechanisms in osteoclast formation.
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The health and economic impact of osteoporosis, a disease characterized by excessive osteoclastic bone resorption, continues to make studies of bone resorption by osteoclasts a critically important research area. Most of what we know about the normal function of the osteoclast comes, paradoxically, from the study of osteopetrosis, a heterogeneous genetic disease characterized by osteoclast failure.1 Osteopetrosis can be the result of reduced osteoclast numbers and/or impaired osteoclast function. While the former indicates a genetic defect that affects osteoclast differentiation, the latter suggests that the mutation affects osteoclast activity. To date, several genes have been demonstrated to be involved in the pathogenesis of the disease in humans. These mutations affect either differentiation (that is, RANKL, RANK) or activity (ATP6i, Clc-7, PLEKHM1 and OSTM1) of osteoclasts. However, approximately 25% of all human osteopetrosis cases are caused by mutations in still unidentified genes. Therefore, the identification of these new genes is critical to improve diagnosis and clinical outcomes. In addition, as each gene is expected to be required for normal osteoclast function, each discovery will lead to a clearer understanding of the molecular mechanisms underlying osteoclast formation and activity and provide new potential therapeutic targets to treat bone diseases.
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Abstract Bone remodelling is process of constant resorption and formation of a bone. Osteoclasts are the cells responsible for bone resorption. Deregulation of osteoclast differentiation, activity or function can cause severe diseases, such as osteoporosis, osteopetrosis or rheumatoid arthritis. Advances in molecular biology of osteoclasts and osteoimmunology open new approaches for the specific and efficient therapy.
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Osteopetrosis
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Multinucleate
Osteopetrosis
Osteoimmunology
Calcitonin receptor
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Abstract Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast-poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single-nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis. © 2012 American Society for Bone and Mineral Research
Osteopetrosis
Osteoimmunology
LYN
Hypogammaglobulinemia
Osteolysis
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New evidence of the interactions between the immune system and bone has accumulated in bone diseases, including osteoporosis, periodontitis and rheumatoid arthritis. A marked imbalance between bone resorption and formation is central to the onset of pathological bone loss. Osteoimmunology has revealed that the immune system, including T cells, B cells and inflammatory cytokines, is a key regulator of both osteoclasts and osteoblasts. Th1 cells, which differentiate from CD4+T cells, are thought to play a major function during bone loss. Moreover, the correlated expression of Th1 cytokines (interleukin-12 (IL-12), interferon-γ (IFN-γ)) and bone-resorbing cytokines (tumor necrosis factor-α (TNF-α), IL-1) also plays a key role during inflammatory induced bone resorption. Furthermore, a relatively new member of the CD4+T cell family Th17 displays the ability to promote osteoclast activity. The effect of IFN-γ and IL-17 released by Th 17 cells on pre-osteoclast proliferation, differentiation and apoptosis provides the preliminary basis for the immune mechanism of pathological bone loss. The role of B cells in osteoimmunological interactions has long been suspected based on findings of B cells as active regulators of the RANK/RANKL/OPG axis. Pathological bone loss, including osteoporosis and human immunodeficiency virus-associated bone loss, are related to the altered RANKL/OPG through modified production by B cells, supporting this assumption. All of the above evidence may provide new theoretical explanations for the relationship between bone metabolism and the immune system as well as offer perspectives for the prevention and treatment of pathological bone loss. Keywords: Bone loss, osteoclast, osteoblast, osteoimmuology, T cells, B cells.
Osteoimmunology
Bone remodeling
Bone cell
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Asymptomatic gene carriers and clinically affected ADO2 subjects have the same ClCN7 mutation. We examined osteoclastic bone resorption in vitro as well as osteoclast formation, several markers, acid secretion, and cytoskeletal structure. We found that ADO2 expression results from osteoclast specific properties.Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. However, of those individuals with a ClCN7 mutation, one third are asymptomatic gene carriers who have no clinical, biochemical, or radiological manifestations. Disease severity in the remaining two thirds is highly variable.Human peripheral blood mononuclear cells were isolated and differentiated into osteoclasts by stimulation with hRANKL and human macrophage-colony stimulating factor (hM-CSF). Study subjects were clinically affected subjects, unaffected gene carriers, and normal controls (n = 6 in each group). Pit formation, TRACP staining, RANKL dose response, osteoclast markers, acid secretion, F-actin ring, and integrin alpha(v)beta3 expression and co-localization were studied.Osteoclasts from clinically affected subjects had severely attenuated bone resorption compared with those from normal controls. However, osteoclasts from unaffected gene carriers displayed similar bone resorption to those from normal controls. In addition, the resorption lacunae from both unaffected gene carriers and normal controls appeared much earlier and spread much more rapidly than those from clinically affected subjects. As time progressed, the distinction between clinically affected subjects and the other two groups increased. No significant difference was found in acidic secretion or osteoclast formation between the three groups. Osteoclast cytoskeletal organization showed no difference between the three groups but there was low cellular motility in clinically affected subjects.Osteoclasts from the unaffected gene carriers, in contrast to those from the clinically affected subjects, functioned normally in cell culture. This finding supports the hypothesis that intrinsic osteoclast factors determine disease expression in ADO2. Further understanding of this mechanism is likely to lead to the development of new approaches to the treatment of clinically affected patients.
Osteopetrosis
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