Ultrastructural investigations of bone resorptive cells in two types of autosomal dominant osteopetrosis

Bollerslev, Jens; Marks, Sandy C.; Pockwinse, Shirwin M.; Kassem, Moustapha; Brixen, Kim; Steiniche, Torben; Mosekilde, Leif

doi:10.1016/8756-3282(93)90316-3

Cited by 67 publications

(79 citation statements)

References 21 publications

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“…The ATP6i patients suffer from a similar but more severe form of osteopetrosis than the ADOII patients. 21 Increased levels of nonresorbing osteoclasts because of impaired acidification with unaltered bone formation or even increased bone formation, are found in the ADOII and ATP6i patients, 21,23,24 as well as in OVX rats treated with a chloride channel inhibitor. Each of these separate cases display increased osteoclast levels, resorption attenuated osteoclasts in the face of bone formation levels similar to or increased compared to control.…”

Section: Discussionmentioning

confidence: 99%

“…Osteoclast levels assessed by serum TRAP measurements 29 and histological evaluation 23 in ADOII patients are increased more than threefold. We have shown previously that although ADOII patients have increased osteoclast numbers 24 the formation of osteoclasts from their CD14-positive monocytes does not differ from those isolated from healthy sex-and age-matched controls.…”

Section: However Acidification and Resorption Are Strongly Impairedmentioning

confidence: 99%

“…18 -22 A further interesting feature found in patients with defective acidification is the presence of increased numbers of abnormally large osteoclasts. [22][23][24] The reason for this phenomenon has never been identified.…”

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Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption

Karsdal

Henriksen

Sørensen

et al. 2005

The American Journal of Pathology

139

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Patients with defective osteoclastic acidification have increased numbers of osteoclasts, with decreased resorption, but bone formation that remains unchanged. We demonstrate that osteoclast survival is increased when acidification is impaired, and that impairment of acidification results in inhibition of bone resorption without inhibition of bone formation. We investigated the role of acidification in human osteoclastic resorption and life span in vitro using inhibitors of chloride channels (NS5818/ NS3696), the proton pump (bafilomycin) and cathepsin K. We found that bafilomycin and NS5818 dose dependently inhibited acidification of the osteoclastic resorption compartment and bone resorption. Inhibition of bone resorption by inhibition of acidification, but not cathepsin K inhibition, augmented osteoclast survival, which resulted in a 150 to 300% increase in osteoclasts compared to controls. We investigated the effect of inhibition of osteoclastic acidification in vivo by using the rat ovariectomy model with twice daily oral dosing of NS3696 at 50 mg/kg for 6 weeks. We observed a 60% decrease in resorption (DPYR), increased tartrate-resistant acid phosphatase levels, and no effect on bone formation evaluated by osteocalcin. We speculate that attenuated acidification inhibits dissolution of the inorganic phase of bone and results in an increased number of nonresorbing osteoclasts that are responsible for the coupling to normal bone formation. Thus, we suggest that acidification is essential for normal bone remodeling and that attenuated acidification leads to uncoupling with decreased bone resorption and unaffected bone formation. The coupling process is understood as a bone formation response that is the consequence of bone resorption, with an amount of bone formed that is equal to that resorbed. 1,2 Uncoupling occurs when the balance between formation and resorption is disturbed, which might lead to either osteopetrosis or osteoporosis. 3,4 Although it has long been appreciated that bone formation is tightly coupled to bone resorption in normal adult bone turnover, 5,6 this coupling can be dissociated in some circumstances, for example during skeletal growth and in some but not all osteopetrotic mutations.Bone consists of two phases, the organic phase, which contains proteins such as collagen type I, and the inorganic phase, which consists of crystallized calcium phosphate. Dissolution of the inorganic phase of bone under the osteoclast attached to the bone surface is a prerequisite for degradation of the organic phase, and is mediated by acidification of the resorption compartment. The decrease in pH necessary to dissolve the inorganic phase is mediated by an active transport of protons over the ruffled border membrane, which is driven by an osteoclastic Vtype H ϩ ATPase. 7,8 At the same time a passive transport of chloride through chloride channels preserves the electroneutrality, 9 and is mediated by the chloride channel ClC-7. 10,11 Degradation of the organic phase of bone is for the major part mediated b...

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Section: Discussionmentioning

confidence: 99%

Section: However Acidification and Resorption Are Strongly Impairedmentioning

confidence: 99%

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Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption

Karsdal

Henriksen

Sørensen

et al. 2005

The American Journal of Pathology

139

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“…Histomorphometry has evidenced normal bone-forming surfaces in very few patients with ADO II. 15 They display a continuous increase in bone density over time, 8 which is compatible with the ongoing bone formation combined with decreased bone resorption. Serum markers of bone formation have not so far been reported in this disease.…”

Section: Discussionmentioning

confidence: 90%

“…8,14 Patients have an increased number of osteoclasts; however, these are unable to form ruffled borders or to resorb bone efficiently. 15 The CLCN7 gene encodes a chloride channel that is a member of the voltage-gated chloride channels family, 3,16 and has Cl À /H þ exchanger properties. 17 It resides mainly in the ruffled border of osteoclasts and in the late endosomes and lysosomes, where it resides with its b-subunit OSTM1.…”

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confidence: 99%

Differentially expressed genes in autosomal dominant osteopetrosis type II osteoclasts reveal known and novel pathways for osteoclast biology

Coudert

Fattore

Baulard

et al. 2014

Laboratory Investigation

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Autosomal dominant osteopetrosis type II (ADO II) is a rare, heritable bone disorder characterized by a high bone mass and insufficient osteoclast activity. Mutations in the CLCN7 gene have been reported to cause ADO II. To gain novel insights into the pathways dysregulated in ADOII osteoclasts, we identified changes in gene expression in osteoclasts from patients with a heterozygous mutation of CLCN7. To do this, we carried out a transcriptomic study comparing gene expression in the osteoclasts of patients with ADO II and healthy donors. Our data show that, according to our selection criteria, 182 genes were differentially expressed in osteoclasts from patients and controls. From the 18 displaying the highest change in microarray, we confirmed differential expression for seven by qPCR. Although two of them have previously been found to be expressed in osteoclasts (ITGB5 and SERPINE2), the other five (CES1 (carboxyl esterase 1), UCHL1 (ubiquitin carboxy-terminal esterase L1, also known as ubiquitin thiolesterase), WARS (tryptophanyl-tRNA synthetase), GBP4 (guanylate-binding protein 4), and PRF1) are not yet known to have a role in this cell type. At the protein level, we confirmed elevated expression of ITGB5 and reduced expression of WARS, PRF1, and SERPINE2. Transfection of ClC-7 harboring the G215R mutation into osteoclasts resulted in an increased ITGB5 and reduced PRF1 expression of borderline significance. Finally, we observed that the ADO II patients presented a normal or increased serum level of bone formation markers, demonstrating a coupling between dysfunctional osteoclasts and osteoblasts. Sphingosine kinase 1 mRNA was expressed at the same level in ADO II and control osteoclasts. In conclusion, these data suggest that in addition to an acidification dysfunction caused by the CLCN7 mutation, a change in ITGB5, PRF1, WARS, and SERPINE2 expression could be part of the osteoclastic phenotype of ADO II.

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Hematopoietic Cell Transplantation for Osteopetrosis

Coccia¹

2003

Thomas' Hematopoietic Cell Transplantation

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Ultrastructural investigations of bone resorptive cells in two types of autosomal dominant osteopetrosis

Cited by 67 publications

References 21 publications

Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption

Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption

Differentially expressed genes in autosomal dominant osteopetrosis type II osteoclasts reveal known and novel pathways for osteoclast biology

Hematopoietic Cell Transplantation for Osteopetrosis

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