Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone

Busse, Björn; Djonić, Danijela; Milovanović, Petar; Hahn, Michael; Püschel, Klaus; Ritchie, Robert O.; Djurić, Marija; Amling, Michael

doi:10.1111/j.1474-9726.2010.00633.x

Cited by 254 publications

(280 citation statements)

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“…28 Our data support the hypothesis that reduced osteocyte viability may increase bone fragility and the number of fractures in MM patients. This is in line with findings in a mouse model showing that estrogen deficiency, which is characterized by reduced osteocyte viability, 22,23 may increase MM cell growth and aggressive bone disease.…”

Section: Discussionsupporting

confidence: 86%

“…The high rate of osteocyte death in all of the biopsy samples was probably because of the median age of our elderly patients, as previously reported by others. 28 The number of dead osteocytes was higher in our MM patients than in the healthy controls, and similar morphological alterations with a reduced number of osteocyte canaliculi have been found in Figure 5. Upregulation of pro-osteoclastogenic cytokines in cocultures of HOB-01 and HMCLs.…”

Section: Discussionsupporting

confidence: 83%

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Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

et al. 2012

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The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast (OCL) formation and bone lesions is still unknown. Osteocytes regulate bone remodelling at least partially, as a result of their cell death triggering OCL recruitment. In this study, we found that the number of viable osteocytes was significantly smaller in MM patients than in healthy controls, and negatively correlated with the number of OCLs. Moreover, the MM patients with bone lesions had a significantly smaller number of viable osteocytes than those without, partly because of increased apoptosis. These findings were further confirmed by ultrastructural in vitro analyses of human preosteocyte cells cocultured with MM cells, which showed that MM cells increased preosteocyte death and apoptosis. A micro-array analysis showed that MM cells affect the transcriptional profiles of preosteocytes by upregulating the production of osteoclastogenic cytokines such as interleukin (IL)-11, and increasing their pro-osteoclastogenic properties. Finally, the osteocyte expression of IL-11 was higher in the MM patients with than in those without bone lesions. Our data suggest that MM patients are characterized by a reduced number of viable osteocytes related to the presence of bone lesions, and that this is involved in MM-induced OCL formation.Leukemia ( Keywords: multiple myeloma; osteocytes; bone disease; osteoclasts INTRODUCTIONThe presence of osteolytic bone lesions or osteoporosis is the hallmark of multiple myeloma (MM), and leads to bone fragility and fractures in MM patients. The bone lesions are characterized by severely unbalanced and uncoupled bone remodelling in the area of plasma cell infiltration due to increased osteoclast (OCL) formation and activity, and osteoblast (OB) suppression. 1 --3 Local factors produced by MM cells and the bone marrow microenvironment are involved in the MM-induced increase in osteoclastogenesis, and include an imbalance in the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio that favours RANKL, 2,4 and the MM cell production of osteoclastogenic factors such as Chemokine (C --C motif) ligand 3 (CCL3)/macrophage inflammatory proteins (MIP)-1a. 5 --7 OB exhaustion is mainly due to a reduction in OB differentiation and formation, from mesenchymal stem cells and OB progenitors, that is induced by MM cells as a result of cell-to-cell contacts and the release of soluble factors. 3,8 --11 Osteocytes are differentiated cells of osteogenic lineage 12 located in the lacuno-canalicular system of the bone (see the review by Bonewald). 13 There is increasing evidence that they regulate physiological local bone remodelling, 13 --16 partly as a result of the cell death and apoptosis that triggers OCL formation and bone resorption, 15 --19 and partly by secreting sclerostin, a molecule that is specifically produced by osteocytes that inhibits bone formation. 20,21 Interestingly, an apoptosis-related reduction in osteocyte viability has recently been demonstrated in

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 83%

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

et al. 2012

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“…The scanning electron microscope (LEO 435 VP, LEO Electron Microscopy Ltd., Cambridge, England) was operated at 15 kV and 665 pA at a constant working distance (BSE Detector, Type 202, K.E. Developments Ltd., Cambridge, England) in line with our previous studies Busse et al, 2010aBusse et al, , 2010b. The pixel size was 3 μm according to the recommendations of Roschger et al (Roschger et al, 2008).…”

Section: Bone Mineral Density Distribution Analysismentioning

confidence: 96%

“…The plastic-embedded block specimens were polished at the surface and carbon coated for scanning electron microscopy and non-destructive microanalysis with EDXA (energy dispersive x-ray analysis; EDAX, DX-4, Mahwah, NJ, USA) allowing spatial investigation of the elemental concentrations (Busse et al, 2010a;Busse et al, 2010b). It is necessary to note that depending on the electron beam settings, damage to the surface of the polished block may occur during the EDXA (Bloebaum et al, 2005).…”

Section: Energy Dispersive X-ray Microanalysismentioning

confidence: 99%

Changes to the cell, tissue and architecture levels in cranial suture synostosis reveal a problem of timing in bone development

Regelsberger¹,

Milovanović²,

Schmidt³

et al. 2012

eCM

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Premature fusion of cranial sutures is a common problem with an incidence of 3-5 per 10,000 live births. Despite progress in understanding molecular/genetic factors affecting suture function, the complex process of premature fusion is still poorly understood. In the present study, corresponding excised segments of nine patent and nine prematurely fused sagittal sutures from infants (age range 3-7 months) with a special emphasis on their hierarchical structural configuration were compared. Cell, tissue and architecture characteristics were analysed by transmitted and polarised light microscopy, 2D-histomorphometry, backscattered electron microscopy and energy-dispersivex-ray analyses. Apart from wider sutural gaps, patent sutures showed histologically increased new bone formation compared to reduced new bone formation and osseous edges with a more mature structure in the fused portions of the sutures. This pattern was accompanied by a lower osteocyte lacunar density and a higher number of evenly mineralised osteons, reflecting pronounced lamellar bone characteristics along the prematurely fused sutures. In contrast, increases in osteocyte lacunar number and size accompanied by mineralisation heterogeneity and randomly oriented collagen fibres predominantly signified woven bone characteristics in patent, still growing suture segments. The already established woven-to-lamellar bone transition provides evidence of advanced bone development in synostotic sutures. Since structural and compositional features of prematurely fused sutures did not show signs of pathological/defective ossification processes, this supports the theory of a normal ossification process in suture synostosis -just locally commencing too early. These histomorphological findings may provide the basis for a better understanding of the pathomechanism of craniosynostosis, and for future strategies to predict suture fusion and to determine surgical intervention.

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“…Osteocytes are the most abundant cells in bone (1)(2)(3), and they are actively involved in the orchestration of both bone-forming osteoblasts and bone-resorbing osteoclasts (4,5). Osteocytes implement their role by activating the signaling pathways involved in the maintenance of bone homeostasis, specifically the Wnt/β-catenin pathway (6).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia mediates osteocyte ORP150 expression and cell death in vitro

Montesi

Jähn

Bonewald

et al. 2016

Molecular Medicine Reports

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Abstract. Skeletal unloading leads to hypoxia in the bone microenvironment, resulting in imbalanced bone remodeling that favors bone resorption. Osteocytes, the mechanosensors of bone, have been demonstrated to orchestrate bone homeostasis. Hypoxic osteocytes either undergo apoptosis or actively stimulate osteoclasts to remove bone matrix during hypoxia. Oxygen-regulated protein 150 (ORP150) is an endoplasmic reticulum-associated chaperone that has been observed to serve an important role in the cellular adaptation to hypoxia and in preventing cellular apoptosis in various tissue types. The current study hypotheses that expression of ORP150 would be increased in osteocytes under hypoxic conditions (1% O 2 ). The MLO-Y4 osteocyte cell line was cultured under normoxic or hypoxic conditions for up to 72 h. It was demonstrated that 1% O 2 significantly induced hypoxia after 16 h and up to 72 h, significantly reduced cell number at 8 and 48 h, induced cell death at 8, 24 and 48 h and induced apoptosis at 16, 24 and 48 h. Significant differences in ORP150 mRNA were observed at 72 h, however no differences were observed in the protein expression levels. The relative increase in ORP150 mRNA observed in hypoxia, compared with normoxia, may support its cytoprotective role in oxygen-deprived conditions.

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Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone

Cited by 254 publications

References 71 publications

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

Changes to the cell, tissue and architecture levels in cranial suture synostosis reveal a problem of timing in bone development

Hypoxia mediates osteocyte ORP150 expression and cell death in vitro

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