RANK-dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations

Pangrazio, Alessandra; Cassani, Barbara; Guerrini, Matteo M.; Crockett, Julie C.; Marrella, Veronica; Zammataro, Luca; Strina, Dario; Schulz, Ansgar; Schlack, Claire; Kornak, Uwe; Mellis, David; Duthie, Angela; Helfrich, Miep; Durandy, Anne; Moshous, Despina; Vellodi, Ashok; Chiesa, Robert; Veys, Paul; Iacono, Nadia Lo; Vezzoni, Paolo; Fischer, Alain; Villa, Anna; Sobacchi, Cristina

doi:10.1002/jbmr.559

Cited by 66 publications

(39 citation statements)

References 24 publications

(51 reference statements)

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“…ARO results from mutations that inhibit either osteoclast formation (osteoclast-poor) or function (osteoclast-rich) [10, 11, 23, 24]. In osteoclast-rich ARO, bone formation by osteoblasts is maintained, or even increased.…”

Section: Beyond Resorption: Regulation Of the Bone Remodeling Cycle Imentioning

confidence: 99%

“…Alternatively, dysfunctional osteoclasts may affect the HSC niche by inhibiting osteoblast differentiation, promoting mesenchymal cell proliferation and/or blocking migration of LSK cells into the BM. The observation that osteoclast-poor ARO patients display only mild hematologic abnormalities argues that dysfunctional osteoclasts may actively prevent the formation of the HSC niche [10, 11, 24]. In support of this model, mouse strains with osteoclast-poor osteopetrosis show higher levels of LSK cells than oc/oc mice [81].…”

Section: Osteoclasts and Other Cells In The Bone Microenvironmentmentioning

confidence: 99%

See 1 more Smart Citation

Osteoclasts: more than ‘bone eaters’

Charles

Aliprantis

2014

Trends in Molecular Medicine

307

250

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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. Here, we highlight functions osteoclasts perform beyond bone resorption. First, we consider how osteoclast signals may contribute to bone formation by osteoblasts and 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. Keywordsosteoclast; osteoblast; bone remodeling; osteopetrosis; osteoporosis; PTH Bone remodeling and osteoclasts 101Bone is a composite tissue of protein and mineral, which undergoes continual remodeling to grow, heal damage, and regulate calcium and phosphate metabolism. This remodeling process is executed by the concerted and sequential effort of bone resorbing osteoclasts and bone forming osteoblasts, acting in what has been termed the basic multicellular unit (BMU) ( Figure 1A). Osteocytes, long-lived osteoblast-derived cells that reside within the bone matrix, monitor bone quality and stress, and coordinate remodeling through membrane bound and secreted factors. Skeletal integrity is maintained throughout the lifespan by matching bone formation and resorption, a process referred to as osteoclast:osteoblast 'coupling.' Coupling is thoroughly summarized in recent excellent reviews [1,2] and in Figure 1.Osteoclasts are multinucleated giant cells that differentiate from myeloid precursors under the influence of the cytokines macrophage colony stimulating factor (MCSF) and receptor © 2014 Elsevier Ltd. All rights reserved.Corresponding Author: Antonios O. Aliprantis, M.D., Ph.D., (AALIPRANTIS@PARTNERS.ORG). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript activator of NF-κB ligand (RANKL) supplied by osteoblasts and/or osteocytes ( Figure 1A) [3]. A decoy receptor for RANKL called osteoprotegrin (OPG), which is also made by the osteoblast lineage, tempers osteoclast differentiation [4]. Osteoclasts degrade bone by the polarized secretion of proteolytic enzymes (e.g. cathepsin K) and acid, which hydrolyze and solubilize the organic and inorganic...

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Section: Beyond Resorption: Regulation Of the Bone Remodeling Cycle Imentioning

confidence: 99%

Section: Osteoclasts and Other Cells In The Bone Microenvironmentmentioning

confidence: 99%

Osteoclasts: more than ‘bone eaters’

Charles

Aliprantis

2014

Trends in Molecular Medicine

307

250

View full text Add to dashboard Cite

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“…Using WES, we were able to detect a deletion in TNFRSF11A gene (P3), despite the limitation of WES analysis in identification of insertions/deletions. Missense and stop codon mutations in TNFRSF11A , also known as RANK, were previously associated with MIOP development in humans . However, in a review of the literature we found no patients with deletions in TNFRSF11A .…”

Section: Discussionmentioning

confidence: 56%

The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis

et al. 2016

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Autosomal recessive malignant infantile osteopetrosis is a congenital disease characterized by pathologically increased bone density. Recently, the use of whole exome sequencing has been utilized as a clinical diagnostic tool in a number of Mendelian disorders. In this study, whole exome sequencing (WES) was successfully used in six patients with malignant infantile osteopetrosis (MIOP) and identified mutations in four MIOP-related genes (CLCN7, TCIRG1, SNX10, and TNFRSF11A). We report these patients, describe the mutations and review the current literature.

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“…Two genes whose mutations are known to cause severe osteopetroses code for the osteoclastogenic cytokine RANKL (TNFSF11) expressed by the osteoblasts, and its receptor RANK (TNFRSF11A) expressed by the osteoclast precursors, accounting for 5% of patients each (55). The RANKL/RANK pathway is implicated in the process of osteoclast formation, therefore these forms of osteopetrosis are osteoclast-poor (24), and in bone biopsies the TRAcP histochemical staining detects no positive cells (25).…”

Section: Recessive Osteopetrosesmentioning

confidence: 99%

Osteopetroses, emphasizing potential approaches to treatment

Teti

Econs

2017

Bone

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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.

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RANK-dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations

Cited by 66 publications

References 24 publications

Osteoclasts: more than ‘bone eaters’

Osteoclasts: more than ‘bone eaters’

The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis

Osteopetroses, emphasizing potential approaches to treatment

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