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  • 1
    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
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2905710-3
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  • 2
    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
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2905710-3
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  • 3
    In: Journal of Bone and Mineral Research, Wiley, Vol. 25, No. 9 ( 2010-09), p. 1980-1987
    Abstract: The C‐variant of a T‐13910C polymorphism (rs4988235; NT_022135.15:g.25316568G  〉  A) upstream of the lactase phlorizin hydrolase (LPH) gene causes lactose intolerance. Association studies with differences in bone parameters and fracture risk have been inconclusive. The objective of this study was to examine the association of LPH rs4988235 with body height and bone parameters and calcium homeostasis in two elderly populations of Dutch Caucasians and assess interaction with vitamin D receptor (VDR) polymorphisms. Genotyping of LPH and VDR polymorphisms was performed in 6367 individuals from the Rotterdam Study and 844 from the Longitudinal Aging Study Amsterdam (LASA). Associations with age, height, weight, bone mineral density (BMD), skeletal morphometric parameters and serum vitamin D and calcium levels, and dietary calcium intake were assessed using ANOVA or analysis of covariance, and allele dose effect was assessed using linear regression analysis. Fracture risk was analyzed using Cox's proportional hazard regression analysis. Associations with body height (p = 2.7 × 10 −8 ) and vertebral area (p = .048) found in the Rotterdam Study were explained by population stratification, as assessed by principal‐component analyses, and disappeared after additional adjustments. No associations with femoral neck or lumbar spine BMD or with fracture risk were detected. Calcium intake and serum ionized serum calcium were significantly lower in C‐homozygotes (p = 9.2 × 10 −7 , p = .02, respectively). For none of the parameters studied was interaction between the T‐13910C polymorphism and VDR block 5 haplotype 1 observed. We show that the C allele of the T‐13910C polymorphism causing lactose intolerance is associated with lower dietary calcium intake and serum calcium levels but not with BMD or fractures. The associations observed with height and vertebral area were the result of population stratification. This demonstrates the impact of population stratification and urges researchers to carefully take this into account in genetic associations, in particular, in dietary intake–related phenotypes, of which LPH and lactose intolerance are a strong example. © 2010 American Society for Bone and Mineral Research
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2010
    detail.hit.zdb_id: 2008867-X
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  • 4
    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
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    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2008867-X
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  • 5
    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
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    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2008867-X
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  • 6
    In: Journal of Bone and Mineral Research, Wiley, Vol. 23, No. 11 ( 2008-11), p. 1815-1824
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 0884-0431
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2008
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  • 7
    In: Journal of Bone and Mineral Research, Wiley, Vol. 35, No. 10 ( 2020-10), p. 1904-1913
    Abstract: Advanced glycation end‐products (AGEs), which bind to type 1 collagen in bone and skin, have been implicated in reduced bone quality. The AGE reader™ measures skin autofluorescence (SAF), which might be regarded as a marker of long‐term accumulation of AGEs in tissues. We investigated the association of SAF with bone mineral density (BMD) and fractures in the general population. We studied 2853 individuals from the Rotterdam Study with available SAF measurements (median age, 74.1 years) and with data on prevalent major osteoporotic (MOFs: hip, humerus, wrist, clinical vertebral) and vertebral fractures (VFs: clinical + radiographic Genant’s grade 2 and 3). Radiographs were assessed 4 to 5 years before SAF. Multivariate regression models were performed adjusted for age, sex, BMI, creatinine, smoking status, and presence of diabetes and additionally for BMD with interaction terms to test for effect modification. Prevalence of MOFs was 8.5% and of VFs 7%. SAF had a curvilinear association with prevalent MOFs and VFs and therefore, age‐adjusted, sex stratified SAF quartiles were used. The odds ratio (OR) (95% confidence interval [CI]) of the second, third and fourth quartiles of SAF for MOFs were as follows: OR 1.60 (95% CI, 1.08–2.35; p = .02); OR 1.30 (95% CI, 0.89–1.97; p = .20), and OR 1.40 (95% CI, 0.95–2.10; p = .09), respectively, with first (lowest) quartile as reference. For VFs the ORs were as follows: OR 1.69 (95% CI, 1.08–2.64; p = .02), OR 1.74(95% CI, 1.11–2.71; p = .01), and OR 1.73 (95% CI, 1.12–2.73; p = .02) for second, third, and fourth quartiles, respectively. When comparing the top three quartiles combined with the first quartile, the OR (95% CI) for MOFs was 1.43 (95% CI, 1.04–2.00; p = .03) and for VFs was 1.72 (95% CI, 1.18–2.53; p = .005). Additional adjustment for BMD did not change the associations. In conclusion, there is evidence of presence of a threshold of skin AGEs below which there is distinctly lower prevalence of fractures. Longitudinal analyses are needed to confirm our cross‐sectional findings. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2008867-X
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  • 8
    In: JBMR Plus, Wiley, Vol. 7, No. 10 ( 2023-10)
    Abstract: Fibroblast growth factor (FGF)23 is one of the major regulators of phosphate homeostasis. Hypophosphatemia can lead to muscle weakness, fatigue, and osteomalacia. In the setting of hypophosphatemia, serum FGF23 can be measured to differentiate between FGF23‐mediated and non‐FGF23‐mediated renal phosphate wasting. C‐terminal FGF23 (cFGF23) assays detect both cFGF23 and intact FGF23 (iFGF23). Circulating FGF23 is regulated by 1.25‐dihydroxy‐vitamin D, parathyroid hormone (PTH), serum phosphate, and serum calcium but also by, for example, iron status, inflammation, erythropoietin, and hypoxia‐inducible‐factor‐1‐α. We present the case of a 48‐year‐old woman with unexplained mild hypophosphatemia, very high cFGF23, and normal iFGF23. The patient proved to have an iron deficiency. Iron deficiency alters the iFGF23‐to‐cFGF23 ratio. After initiation of iron treatment, cFGF23 strongly decreased. This case report illustrates the limitation of cFGF23 assays and urges clinicians to be aware that cFGF23 concentrations do not necessarily reflect iFGF23 concentrations and that alternative causes for its elevation should be considered (eg, iron deficiency). © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
    Type of Medium: Online Resource
    ISSN: 2473-4039 , 2473-4039
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2905710-3
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