| 1. |
- Amzaleg, Y., et al.
(författare)
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Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells
- 2018
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 183, s. 10-17
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens attenuate bone turnover by inhibiting both osteoclasts and osteoblasts, in part through antagonizing Runx2. Apparently conflicting, stimulatory effects in osteoblast lineage cells, however, sway the balance between bone resorption and bone formation in favor of the latter. Consistent with this dualism, 17 beta-estradiol (E2) both stimulates and inhibits Runx2 in a locus-specific manner, and here we provide evidence for such locus specific regulation of Runx2 by E2 in vivo. We also demonstrate dual, negative and positive, regulation of Runx2-driven alkaline phosphatase (ALP) activity by increasing E2 concentrations in ST2 osteoblast progenitor cells. We further compared the effects of E2 to those of the Selective Estrogen Receptor Modulators (SERMs) raloxifene (ral) and lasofoxifene (las) and the phytoestrogen puerarin. We found that E2 at the physiological concentrations of 0.1-1 nM, as well as ral and las, but not puerarin, antagonize Runx2-driven ALP activity. At >= 10 nM, E2 and puerarin, but not ral or las, stimulate ALP relative to the activity measured at 0.1-1 nM. Contrasting the difference between E2 and SERMs in ST2 cells, they all shared a similar dose-response profile when inhibiting preosteoclast proliferation. That ral and las poorly mimic the locus-and concentration-dependent effects of E2 in mesenchymal progenitor cells may help explain their limited clinical efficacy.
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| 2. |
- Staines, K. A., et al.
(författare)
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Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis
- 2019
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Ingår i: Bmc Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSubchondral bone (SCB) thickening is one of the earliest detectable changes in osteoarthritic joints and is considered a potential trigger for subsequent articular cartilage degeneration. In this manuscript, we examine whether disruption to the SCB osteocyte network contributes to the initiation and pathogenesis of osteoarthritis.MethodsWe examined expression patterns of the glycoprotein E11/podoplanin by immunohistochemical labelling in murine, human and canine osteoarthritis models. We also examined the effects of twice-weekly administration of Bortezomib, a proteasome inhibitor which stabilises osteocyte E11 levels, to C57/BL6 wild-type male mice (1mg/kg/day) for 8weeks after surgical destabilisation of the medial meniscus. By inducing osteoarthritis-like changes in the right knee joint of 12-week-old male E11 hypomorphic mice (and corresponding controls) using a post-traumatic joint loading model, we also investigated whether a bone-specific E11 deletion in mice increases joint vulnerability to osteoarthritis. Articular cartilage degradation and osteophyte formation were assessed by histology and in line with the OARSI grading system.ResultsOur studies reveal increased E11 expression in osteocytes of human and canine osteoarthritic SCB. We found that Bortezomib administration had no effect on surgically-induced osteoarthritis, potentially due to a lack of the expected stabilisation of E11 in the SCB. We also found, in concordance with our previous work, wild-type mice exhibited significant load-induced articular cartilage lesions on the lateral femoral condyle (p<0.01) and osteophyte formation. In contrast, E11 hypomorphic mice did not develop osteophytes or any corresponding articular lesions.ConclusionsOverall, these data suggest that an intact osteocyte network in the SCB contributes to the development of mechanically-driven osteoarthritis. Further, the data presented here indicate that the molecular pathways that preserve the osteocyte network, such as those driven by E11, may be targeted to limit osteoarthritis pathogenesis.
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| 3. |
- Bergström, I., et al.
(författare)
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Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone
- 2017
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 28:3, s. 1121-1131
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Loading increases bone mass and strength in a site-specific manner; however, possible effects of loading on bone matrix composition have not been evaluated. Site-specific structural and material properties of mouse bone were analyzed on the macro- and micro/molecular scale in the presence and absence of axial loading. The response of bone to load is heterogeneous, adapting at molecular, micro-, and macro-levels. Introduction: Osteoporosis is a degenerative disease resulting in reduced bone mineral density, structure, and strength. The overall aim was to explore the hypothesis that changes in loading environment result in site-specific adaptations at molecular/micro- and macro-scale in mouse bone. Methods: Right tibiae of adult mice were subjected to well-defined cyclic axial loading for 2 weeks; left tibiae were used as physiologically loaded controls. The bones were analyzed with μCT (structure), reference point indentation (material properties), Raman spectroscopy (chemical), and small-angle X-ray scattering (mineral crystallization and structure). Results: The cranial and caudal sites of tibiae are structurally and biochemically different within control bones. In response to loading, cranial and caudal sites increase in cortical thickness with reduced mineralization (−14 and −3%, p < 0.01, respectively) and crystallinity (−1.4 and −0.3%, p < 0.05, respectively). Along the length of the loaded bones, collagen content becomes more heterogeneous on the caudal site and the mineral/collagen increases distally at both sites. Conclusion: Bone structure and composition are heterogeneous, finely tuned, adaptive, and site-specifically responsive at the micro-scale to maintain optimal function. Manipulation of this heterogeneity may affect bone strength, relative to specific applied loads.
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| 4. |
- Audouin, L., et al.
(författare)
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High-precision measurement of isotopic fission yields of 236 U
- 2018
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Ingår i: EPJ Web of Conferences. - : EDP Sciences. - 2101-6275 .- 2100-014X. ; 193
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Konferensbidrag (refereegranskat)abstract
- We report on the second SOFIA experiment, dedicated to the fission yields of 236U∗, analog to 235U(n,f). The measurement is based on the inverse kinematics method, using a relativistic, secondary beam of 236U. Both fission fragments are identified in mass and charge in the SOFIA recoil spectrometer. The obtained isotopic yields are compared with existing spectroscopy measurements and the elemental yields are used to discuss the treatment of the even-odd effect with energy in nuclear data libraries.
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| 5. |
- Tollemar, V, et al.
(författare)
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Quantitative chromogenic immunohistochemical image analysis in cellprofiler software.
- 2018
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Ingår i: Cytometry Part A. - : John Wiley & Sons. - 1552-4922 .- 1552-4930. ; 93:10, s. 1051-1059
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Tidskriftsartikel (refereegranskat)abstract
- Visual grading of chromogenically stained immunohistochemical (IHC) samples is subjective, time consuming, and predisposed to considerable inter- and intra-observer variations. The open-source digital analysis software, CellProfiler has been extensively used for fluorescently stained cells/tissues; however, chromogenic IHC staining is routinely used in both pathological and research diagnostics. The current investigation aimed to compare CellProfiler quantitative chromogenic IHC analyses against the gold standard manual counting. Oral mucosal biopsies from patients with chronic graft-versus-host disease were stained for CD4. Digitized images were manually counted and subjected to image analysis in CellProfiler. Inter-observer and inter-platform agreements were assessed by scatterplots with linear regression and Bland-Altman plots. Validation comparisons between the manual counters demonstrated strong intra-observer concordance (r(2) = 0.979), particularly when cell numbers were less than 100. Scatterplots and Bland-Altman plots demonstrated strong agreement between the manual counters and CellProfiler, with the number of positively stained cells robustly correlating (r(2) = 0.938). Furthermore, CellProfiler allowed the determination of multiple variables simultaneously, such as area stained and masking to remove any nonstained tissue and white gaps, which also demonstrated reliable agreement (r(2) = >0.9). CellProfiler demonstrated versatility with the ability to assess large numbers of images and allowed additional parameters to be quantified. CellProfiler allowed rapid high processing capacity of chromogenically stained chronic inflammatory tissue that was reliable, accurate, and reproducible and highlights potential applications in research diagnostics.
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