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  • 1
    Online Resource
    Online Resource
    Identification of Chloride Intracellular Channel Protein 3 as a Novel Gene Affecting Human Bone Formation
    Wiley ; 2017
    In:  JBMR Plus Vol. 1, No. 1 ( 2017-08), p. 16-26
    Details
    In: JBMR Plus, Wiley, Vol. 1, No. 1 ( 2017-08), p. 16-26
    Abstract: Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. The bone building cells, osteoblasts, are derived from mesenchymal stromal cells (MSCs); however, with increasing age osteogenic differentiation is diminished and more adipocytes are seen in the bone marrow, suggesting a shift in MSC lineage commitment. Identification of specific factors that stimulate osteoblast differentiation from human MSCs may deliver therapeutic targets to treat osteoporosis. The aim of this study was to identify novel genes involved in osteoblast differentiation of human bone marrow–derived MSCs (hMSCs). We identified the gene chloride intracellular channel protein 3 ( CLIC3 ) to be strongly upregulated during MSC‐derived osteoblast differentiation. Lentiviral overexpression of CLIC3 in hMSCs caused a 60% increase of matrix mineralization. Conversely, knockdown of CLIC3 in hMSCs using two short‐hairpin RNAs (shRNAs) against CLIC3 resulted in a 69% to 76% reduction in CLIC3 mRNA expression, 53% to 37% less alkaline phosphatase (ALP) activity, and 78% to 88% less matrix mineralization compared to scrambled control. Next, we used an in vivo human bone formation model in which hMSCs lentivirally transduced with the CLIC3 overexpression construct were loaded onto a scaffold (hydroxyapatite‐tricalcium‐phosphate), implanted under the skin of NOD‐SCID mice, and analyzed for bone formation 8 weeks later. CLIC3 overexpression led to a 15‐fold increase in bone formation (0.33% versus 5.05% bone area relative to scaffold). Using a Clic3‐His‐tagged pull‐down assay and liquid chromatography–mass spectrometry (LS/MS)‐based proteomics analysis in lysates of osteogenically differentiated hMSCs, we showed that CLIC3 interacts with NIMA‐related kinase 9 (NEK9) and phosphatidylserine synthase 1 (PTDSS1) in vitro, and this finding was supported by immunofluorescent analysis. In addition, inhibition of NEK9 or PTDSS1 gene expression by shRNAs inhibited osteoblast differentiation and mineralization. In conclusion, we successfully identified CLIC3 to be a lineage‐specific gene regulating osteoblast differentiation and bone formation through its interaction with NEK9 and PTDSS1. © The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
    Type of Medium: Online Resource
    ISSN: 2473-4039 , 2473-4039
    URL: Issue
    URL: Article
    DOI: 10.1002/jbm4.v1.1
    DOI: 10.1002/jbm4.10003
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2905710-3
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  • 2
    Online Resource
    Online Resource
    Mucin 1 (Muc1) Deficiency in Female Mice Leads to Temporal Skeletal Changes During Aging
    Wiley ; 2018
    In:  JBMR Plus Vol. 2, No. 6 ( 2018-11), p. 341-350
    Details
    In: JBMR Plus, Wiley, Vol. 2, No. 6 ( 2018-11), p. 341-350
    Abstract: Mucin1 (MUC1) encodes a glycoprotein that has been demonstrated to have important roles in cell‐cell interactions, cell‐matrix interactions, cell signaling, modulating tumor progression and metastasis, and providing physical protection to cells against pathogens. In this study, we investigated the bone phenotype in female C57BL/6 Muc1 null mice and the impact of the loss of Muc1 on osteoblasts and osteoclasts. We found that deletion of Muc1 results in reduced trabecular bone volume in 8‐week‐old mice compared with wild‐type controls, but the trabecular bone volume fraction normalizes with increasing age. In mature female mice (16 weeks old), Muc1 deletion results in stiffer femoral bones with fewer osteoblasts lining the trabecular surface but increased endosteal mineralized surface and bone formation rate. The latter remains higher compared with wild‐type females at age 52 weeks. No difference was found in osteoclast numbers in vivo and in bone marrow osteoblast or osteoclast differentiation capacity or activity in vitro. Taken together, these results suggest that Muc1 depletion causes a transiently reduced trabecular bone mass phenotype in young mice, and later in life reduced numbers of osteoblasts with increased endocortical mineralization activity coincides with unaffected total bone mass and increased stiffness. In conclusion, our results show, for the first time to our knowledge, a role for Muc1 in bone mass and mineralization in mice in a time‐dependent manner. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
    Type of Medium: Online Resource
    ISSN: 2473-4039 , 2473-4039
    URL: Issue
    URL: Article
    DOI: 10.1002/jbm4.v2.6
    DOI: 10.1002/jbm4.10061
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2905710-3
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  • 3
    Online Resource
    Online Resource
    Serum Phosphate Is Associated With Fracture Risk: The Rotterdam Study and MrOS
    Wiley ; 2017
    In:  Journal of Bone and Mineral Research Vol. 32, No. 6 ( 2017-06), p. 1182-1193
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 32, No. 6 ( 2017-06), p. 1182-1193
    Abstract: Extreme phosphate levels (P) have been associated with mineralization defects and increased fracture risk. Whether P within normal range is related to bone health in the general population is not well understood. To investigate the association of P with bone mineral density (BMD) and fracture risk, we assessed two population‐based cohorts: the Dutch Rotterdam Study (RS‐I, RS‐II, RS‐III; n  = 6791) and the US Osteoporotic Fractures in Men (MrOS; n  = 5425) study. The relationship of P with lumbar spine (LS) and femoral neck (FN) BMD was tested in all cohorts via linear models; fracture risk was tested in RS‐I, RS‐II, and MrOS through Cox models, after follow‐up of 8.6, 6.6, and 10.9 years, respectively. Adjustments were made for age, body mass index, smoking, serum levels of calcium, potassium, 25‐hydroxyvitamin D, estimated glomerular filtration rate (eGFR), FN‐BMD, prevalent diabetes, and cardiovascular disease. Additional adjustments were made for phosphate intake, parathyroid hormone, and fibroblast growth factor 23 levels in MrOS. We further stratified by eGFR. Results were pooled through study‐level meta‐analyses. Hazard ratios (HR) and betas (β) (from meta‐analyses) are expressed per 1 mg/dL P increase. P was positively associated with fracture risk in men and women from RS, and findings were replicated in MrOS (pooled HR all [95% CI]: 1.47 [1.31–1.65] ). P was associated with fracture risk in subjects without chronic kidney disease (CKD): all (1.44 [1.26–1.63]) and in men with CKD (1.93 [1.42–2.62] ). P was inversely related to LS‐BMD in men (β: –0.06 [–0.11 to –0.02]) and not to FN‐BMD in either sex. In summary, serum P was positively related to fracture risk independently from BMD and phosphate intake after adjustments for potential confounders. P and LS‐BMD were negatively related in men. Our findings suggest that increased P levels even within normal range might be deleterious for bone health in the normal population. © 2017 American Society for Bone and Mineral Research.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Issue
    URL: Article
    DOI: 10.1002/jbmr.v32.6
    DOI: 10.1002/jbmr.3094
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2008867-X
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  • 4
    Online Resource
    Online Resource
    Understanding Age‐Induced Cortical Porosity in Women: The Accumulation and Coalescence of Eroded Cavities Upon Existing Intracortical Canals Is the Main Contributor
    Wiley ; 2018
    In:  Journal of Bone and Mineral Research Vol. 33, No. 4 ( 2018-04), p. 606-620
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 33, No. 4 ( 2018-04), p. 606-620
    Abstract: Intracortical bone remodeling normally ensures maintenance of the cortical bone matrix and strength, but during aging, this remodeling generates excessive porosity. The mechanism behind the age‐induced cortical porosity is poorly understood and addressed in the present study. This study consists of a histomorphometric analysis of sections of iliac bone specimens from 35 women (age 16–78 years). First, the study shows that the age‐induced cortical porosity reflects an increased pore size rather than an increased pore density. Second, it establishes a novel histomorphometric classification of the pores, which is based on the characteristics of the remodeling sites to which each pore is associated. It takes into consideration (i) the stage of the remodeling event at the level where the pore is sectioned, (ii) whether the event corresponds with the generation of a new pore through penetrative tunneling (type 1 pores) or with remodeling of an existing pore (type 2 pores), and (iii) in the latter case, whether or not the new remodeling event leads to the coalescence of pores. Of note, the advantage of this classification is to relate porosity with its generation mechanism. Third, it demonstrates that aging and porosity are correlated with: a shift from type 1 to type 2 pores, reflecting that the remodeling of existing pores is higher; an accumulation of eroded type 2 pores, reflecting an extended resorption‐reversal phase; and a coalescence of these eroded type 2 pores into enlarged coalescing type 2 cavities. Collectively, this study supports the notion, that age‐related increase in cortical porosity is the result of intracortical remodeling sites upon existing pores, with an extended reversal‐resorption phase (eroded type 2 pores) that may likely result in a delayed or absent initiation of the subsequent bone formation. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Issue
    URL: Article
    DOI: 10.1002/jbmr.v33.4
    DOI: 10.1002/jbmr.3354
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2008867-X
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  • 5
    Online Resource
    Online Resource
    Dexamethasone in osteogenic medium strongly induces adipocyte differentiation of mouse bone marrow stromal cells and increases osteoblast differentiation
    Springer Science and Business Media LLC ; 2015
    In:  BMC Cell Biology Vol. 16, No. 1 ( 2015-12)
    Details
    In: BMC Cell Biology, Springer Science and Business Media LLC, Vol. 16, No. 1 ( 2015-12)
    Type of Medium: Online Resource
    ISSN: 1471-2121
    URL: Article
    DOI: 10.1186/s12860-015-0056-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 2964981-X
    detail.hit.zdb_id: 2041486-9
    SSG: 12
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