Cortical bone remodeling in autosomal dominant osteopetrosis: A study of two different phenotypes

Brockstedt, H.; Bollerslev, Jens; Melsen, F.; Mosekilde, Lis

doi:10.1016/8756-3282(95)00424-6

Cited by 46 publications

(35 citation statements)

References 19 publications

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“…In all patients, clinical symptoms progressed, whereas the carrier remained asymptomatic (20). The progression of symptoms is in alignment with progression of the universal osteosclerosis, as indicated by cross-sectional studies using DXA and histomorphometry (11,12,20,21,23).…”

Section: Summary Of Recent Systematic Clinical Studiesmentioning

confidence: 81%

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Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Section: Summary Of Recent Systematic Clinical Studiesmentioning

confidence: 81%

“…Early studies at the trabecular (11) and cortical envelope (23) indicated virtually normal bone remodeling and an endosteal resorption defect. However, the studies were limited by few individuals investigated and the immense analytical variability of histomorphometry with the risk of a type 2 error (35).…”

Section: Bone Remodelingmentioning

confidence: 99%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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“…This is verified by the finding of a significant increase in bone formation investigated by mineralized surface index in ADOII patients. 42 In conjunction, by inhibition of osteoclastic acidification in vivo by bafilomycin in new bone implants in a rat model, a massive increase in new bone formation was observed. 43 The cathepsin K-deficient patients (pycnodysostosis) and the cathepsin K-null mutation mice that develop osteopetrosis because of a deficit in matrix degradation, but not demineralization 14,16,44 do not display increased levels of osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

“…This could be explained by a reduced release of factors during resorption (Figure 8B), thus explaining the increased numbers of nonresorbing osteoclasts present in ADOII and ATP6i patients. 24,42 The increased numbers of osteoclasts could result in an increased supply of signal(s) created directly by the osteoclasts ( Figure 8B) which continue signaling for bone formation.…”

Section: Discussionmentioning

confidence: 99%

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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“…The value of R was set to be 150 µm, the average osteon radius (Brockstedt et al, 1996), since it was assumed that the latter is associated with the physical limits of nutrient perfusion and osteocyte action reach 2 .…”

Section: Proposed Mechanobiological Modelmentioning

confidence: 99%

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Supplemental Information 1: Figure S1 and Figure S2

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The development of predictive mathematical models can contribute to a deeper understanding of the specific stages of bone mechanobiology and the process by which bone adapts to mechanical forces. The objective of this work was to predict, with spatial accuracy, cortical bone adaptation to mechanical load, in order to better understand the mechanical cues that might be driving adaptation.The axial tibial loading model was used to trigger cortical bone adaptation in C57BL/6 mice and provide relevant biological and biomechanical information.A method for mapping cortical thickness in the mouse tibia diaphysis was developed, allowing for a thorough spatial description of where bone adaptation occurs.Poroelastic finite-element (FE) models were used to determine the structural response of the tibia upon axial loading and interstitial fluid velocity as the mechanical stimulus. FE models were coupled with mechanobiological governing equations, which accounted for non-static loads and assumed that bone responds instantly to local mechanical cues in an on-off manner. PrePrintsThe presented formulation was able to simulate the areas of adaptation and accurately reproduce the distributions of cortical thickening observed in the experimental data with a statistically significant positive correlation (Kendall's tau rank coefficient τ = 0.51, p < 0.001).This work demonstrates that computational models can spatially predict cortical bone mechanoadaptation to time variant stimulus. Such models could be used in the design of more efficient loading protocols and drugs therapies that target the relevant physiological mechanisms.

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Cortical bone remodeling in autosomal dominant osteopetrosis: A study of two different phenotypes

Cited by 46 publications

References 19 publications

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

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

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