175 results on '"Kuhn, Gisela"'
Search Results
2. Elucidating the mechano-molecular dynamics of TRAP activity using CRISPR/Cas9 mediated fluorescent reporter mice
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Yılmaz, Dilara, Marques, Francisco C., Fischer, Yannick, Zimmermann, Sandra, Hwang, Gaonhae, Atkins, Penny R., Mathavan, Neashan, Singh, Amit, de Souza, Pedro P.C., Kuhn, Gisela A., Wehrle, Esther, and Müller, Ralph
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- 2024
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3. Mesenchyme-derived vertebrate lonesome kinase controls lung organogenesis by altering the matrisome
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Brütsch, Salome M., Madzharova, Elizabeta, Pantasis, Sophia, Wüstemann, Till, Gurri, Selina, Steenbock, Heiko, Gazdhar, Amiq, Kuhn, Gisela, Angel, Peter, Bellusci, Saverio, Brinckmann, Jürgen, auf dem Keller, Ulrich, Werner, Sabine, and Bordoli, Mattia R.
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- 2023
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4. The major urinary protein gene cluster knockout mouse as a novel model for translational metabolism research
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Greve, Sarah, Kuhn, Gisela A., Saenz-de-Juano, Mara D., Ghosh, Adhideb, von Meyenn, Ferdinand, and Giller, Katrin
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- 2022
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5. Unveiling frailty: comprehensive and sex-specific characterization in prematurely aging PolgA mice.
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Yılmaz, Dilara, Singh, Amit, Wehrle, Esther, Kuhn, Gisela A., Mathavan, Neashan, and Müller, Ralph
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WEIGHT loss ,RESEARCH funding ,T-test (Statistics) ,DATA analysis ,FRAIL elderly ,SEX distribution ,FISHER exact test ,DIAGNOSIS ,GAIT in humans ,MANN Whitney U Test ,DESCRIPTIVE statistics ,MICE ,AGING ,GERIATRIC assessment ,ANIMAL experimentation ,ANALYSIS of variance ,STATISTICS ,WALKING speed ,DATA analysis software ,COMPARATIVE studies ,PHYSICAL activity ,GRIP strength - Abstract
Frailty, a geriatric syndrome, is assessed using the frailty phenotype (FP) and frailty index (FI). While these approaches have been applied to aging mice, their effectiveness in prematurely aging mouse models such as PolgA
D257A/D257A (PolgA) has not been completely explored. We demonstrated that frailty became evident in PolgA mice around 40 weeks, validated through body weight loss, reduced walking speed, decreased physical activity, and weaker grip strength. Moreover, we also identified sex differences in these mice with females exhibiting slightly more physical decline compared to males. Frailty prevalence in PolgA mice at 40 weeks parallels that observed in naturally aging mice at 27 months and aging humans at 65-70 years. These findings contribute to understanding frailty onset and sex-specific patterns in this prematurely aging mouse model, emphasizing the significance of the PolgA mouse model in investigating aging and related disorders. [ABSTRACT FROM AUTHOR]- Published
- 2024
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6. Daily rhythms in metabolic and locomotor behaviour of prematurely ageing PolgA mice.
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Singh, Amit, Yilmaz, Dilara, Wehrle, Esther, Kuhn, Gisela A., and Müller, Ralph
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WALKING speed ,DRINKING (Physiology) ,GRIP strength ,HUMAN phenotype ,CARBOHYDRATE metabolism ,OXYGEN consumption - Abstract
Ageing is an inherent and intricate biological process that takes place in living organisms as time progresses. It involves the decline of multiple physiological functions, leading to body structure and overall performance modifications. The ageing process differs among individuals and is influenced by various factors, including lifestyle, environment and genetic makeup. Metabolic changes and reduced locomotor activity are common hallmarks of ageing. Our study focuses on exploring these phenomena in prematurely ageing PolgA(D257A/D257A) mice (also known as PolgA) aged 41–42 weeks, as they closely mimic human ageing. We assess parameters such as oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (RER) and locomotor activity using a metabolic cage for 4 days and comparing them with age‐matched wild‐type littermates (WT). Our findings revealed that VO2, VCO2, RER, locomotor activities, water intake and feeding behaviour show a daily rhythm, aligning with roughly a 24‐h cycle. We observed that the RER was significantly increased in PolgA mice compared to WT mice during the night‐time of the light–dark cycle, suggesting a shift towards a higher reliance on carbohydrate metabolism due to more food intake during the active phase. Additionally, female PolgA mice displayed a distinct phenotype with reduced walking speed, walking distance, body weight and grip strength in comparison to male PolgA and WT mice, indicating an early sign of ageing. Taken together, our research highlights the impact of sex‐specific patterns on ageing traits in PolgA mice aged 41–42 weeks, which may be attributable to human ageing phenotypes. The unique genetic composition and accelerated ageing characteristics of PolgA mice make them invaluable in ageing studies, facilitating the investigation of underlying biological mechanisms and the identification of potential therapeutic targets for age‐related diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Real-time finite element analysis allows homogenization of tissue scale strains and reduces variance in a mouse defect healing model
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Paul, Graeme R., Wehrle, Esther, Tourolle, Duncan C., Kuhn, Gisela A., and Müller, Ralph
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- 2021
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8. Application of subject-specific adaptive mechanical loading for bone healing in a mouse tail vertebral defect
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Malhotra, Angad, Walle, Matthias, Paul, Graeme R., Kuhn, Gisela A., and Müller, Ralph
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- 2021
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9. Individualized cyclic mechanical loading improves callus properties during the remodelling phase of fracture healing in mice as assessed from time-lapsed in vivo imaging
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Wehrle, Esther, Paul, Graeme R., Tourolle né Betts, Duncan C., Kuhn, Gisela A., and Müller, Ralph
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- 2021
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10. Spatio-temporal characterization of fracture healing patterns and assessment of biomaterials by time-lapsed in vivo micro-computed tomography
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Wehrle, Esther, Tourolle né Betts, Duncan C., Kuhn, Gisela A., Floreani, Erica, Nambiar, Malavika H., Schroeder, Bryant J., Hofmann, Sandra, and Müller, Ralph
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- 2021
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11. The association between mineralised tissue formation and the mechanical local in vivo environment: Time-lapsed quantification of a mouse defect healing model
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Tourolle né Betts, Duncan C., Wehrle, Esther, Paul, Graeme R., Kuhn, Gisela A., Christen, Patrik, Hofmann, Sandra, and Müller, Ralph
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- 2020
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12. Evaluation of longitudinal time-lapsed in vivo micro-CT for monitoring fracture healing in mouse femur defect models
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Wehrle, Esther, Tourolle né Betts, Duncan C., Kuhn, Gisela A., Scheuren, Ariane C., Hofmann, Sandra, and Müller, Ralph
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- 2019
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13. Microvascular Disease Associates with Larger Osteocyte Lacunae in Cortical Bone in Type 2 Diabetes Mellitus.
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Zanner, Sebastian, Goff, Elliott, Ghatan, Samuel, Wölfel, Eva Maria, Ejersted, Charlotte, Kuhn, Gisela, Müller, Ralph, and Frost, Morten
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COMPACT bone ,TYPE 2 diabetes ,BONE mechanics ,BONE resorption ,BONE growth ,CANCELLOUS bone ,GLYCOSYLATED hemoglobin - Abstract
Clinical studies indicate that microvascular disease (MVD) affects bone microstructure and decreases bone strength in type 2 diabetes mellitus (T2D). Osteocytes are housed in small voids within the bone matrix and lacunae and act as sensors of mechanical forces in bone. These cells regulate osteoclastic bone resorption and osteoblastic bone formation as well as osteocytic perilacunar remodeling. We hypothesized that MVD changes morphometric osteocyte lacunar parameters in individuals with T2D. We collected iliac crest bone biopsies from 35 individuals (10 female, 25 male) with T2D with MVD (15%) or without MVD (21%) with a median age of 67 years (interquartile range [IQR] 62–72 years). The participants were included based on c‐peptide levels >700 pmol L−1, absence of anti‐GAD65 antibodies, and glycated hemoglobin (HbA1c) levels between 40 and 82 mmol mol−1 or 5.8% and 9.7%, respectively. We assessed osteocyte lacunar morphometric parameters in trabecular and cortical bone regions using micro‐computed tomography (micro‐CT) at a nominal resolution of 1.2 μm voxel size. The cortical osteocyte lacunar volume (Lc.V) was 7.7% larger (p = 0.05) and more spherical (Lc.Sr, p < 0.01) in the T2D + MVD group. Using linear regression, we found that lacunar density (Lc.N/BV) in trabecular but not cortical bone was associated with HbA1c (p < 0.05, R2 = 0.067) independently of MVD. Furthermore, Lc.V was larger and Lc.Sr higher in the center than in the periphery of the trabecular and cortical bone regions (p < 0.05). In conclusion, these data imply that MVD may impair skeletal integrity, possibly contributing to increased skeletal fragility in T2D complicated by MVD. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Computational modelling of bone augmentation in the spine
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Badilatti, Sandro D., Kuhn, Gisela A., Ferguson, Stephen J., and Müller, Ralph
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- 2015
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15. Bioluminescent and micro-computed tomography imaging of bone repair induced by fibrin-binding growth factors
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Vila, Olaia F., Martino, Mikaël M., Nebuloni, Laura, Kuhn, Gisela, Pérez-Amodio, Soledad, Müller, Ralph, Hubbell, Jeffrey A., Rubio, Nuria, and Blanco, Jerónimo
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- 2014
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16. Therapeutic potential of adipose-derived stromal cells in age-related osteoporosis
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Mirsaidi, Ali, Genelin, Konstantin, Vetsch, Jolanda R., Stanger, Scott, Theiss, Felix, Lindtner, Richard A., von Rechenberg, Brigitte, Blauth, Michael, Müller, Ralph, Kuhn, Gisela A., Hofmann Boss, Sandra, Ebner, Hannes L., and Richards, Peter J.
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- 2014
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17. Tissue-Level Regeneration and Remodeling Dynamics are Driven by Mechanical Stimuli in the Microenvironment in a Post-Bridging Loaded Femur Defect Healing Model in Mice
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Paul, Graeme R., Vallaster, Paul, Rüegg, Michelle, Scheuren, Ariane C., Tourolle, Duncan C., Kuhn, Gisela A., Wehrle, Esther, and Müller, Ralph
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multi-density analysis ,adaptive loading ,bone ,mechanobiology ,fracture healing ,real-time finite element analysis ,microenvironment ,Cell Biology ,Developmental Biology - Abstract
Bone healing and remodeling are mechanically driven processes. While the generalized response to mechanical stimulation in bone is well-understood, much less is known about the mechanobiology-regulating tissue-scale bone formation and resorption during the reparative and remodeling phases of fracture healing. In this study, we combined computational approaches in the form of finite element analysis and experimental approaches by using a loaded femoral defect model in mice to investigate the role of mechanical stimulation in the microenvironment of bone. Specifically, we used longitudinal micro-computed tomography to observe temporal changes in bone at different densities and micro-finite element analysis to map the mechanics of the microenvironment to tissue-scale formation, quiescence (no change in bone presence between time points), and resorption dynamics in the late reparative and remodeling phases (post bridging). Increasing levels of effective strain led to increasing conditional probability of bone formation, while decreasing levels of effective strain led to increasing probability of bone resorption. In addition, the analysis of mineralization dynamics showed both a temporal and effective strain level-dependent behavior. A logarithmic-like response was displayed, where the conditional probability of bone formation or resorption increased rapidly and plateaued or fell rapidly and plateaued as mechanical strain increased., Frontiers in Cell and Developmental Biology, 10, ISSN:2296-634X
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- 2022
18. A Comparative Analysis of Water-Soluble and Blood-Pool Contrast Agents for in vivo Vascular Imaging with Micro-CT
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Nebuloni, Laura, Kuhn, Gisela A., and Müller, Ralph
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- 2013
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19. Low dose BMP-2 treatment for bone repair using a PEGylated fibrinogen hydrogel matrix
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Ben-David, Dror, Srouji, Samer, Shapira-Schweitzer, Keren, Kossover, Olga, Ivanir, Eran, Kuhn, Gisela, Müller, Ralph, Seliktar, Dror, and Livne, Erella
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- 2013
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20. Degenerative Changes in the Osteocyte Network in Prematurely Aging PolgA Mice
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Yilmaz, Dilara, Gregorio, Lorena, Gehre, Christian P., Whittier, Danielle, Qin, Xiao-Hua, Wehrle, Esther M., Kuhn, Gisela A., and Müller, Ralph
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- 2022
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21. Evaluation of a CRISPR/Cas9-based dual-fluorescent reporter mouse model of premature aging to investigate the mechanobiology of bone regeneration
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Mathavan, Neashan, Gregorio, Lorena, Yilmaz, Dilara, Marques, Francisco Correia, Kuhn, Gisela A., Müller, Ralph, and Wehrle, Esther
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- 2022
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22. Hallmarks of frailty and osteosarcopenia in prematurely aged PolgA(D257A/D257A) mice
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Scheuren, Ariane C., D'Hulst, Gommaar, Kuhn, Gisela A., Masschelein, Evi, Wehrle, Esther, De Bock, Katrien, and Müller, Ralph
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Aging ,Sarcopenia ,lcsh:Diseases of the musculoskeletal system ,in vivo micro‐CT ,Osteopenia ,Osteosarcopenia ,lcsh:Human anatomy ,lcsh:RC925-935 ,mTORC1 ,lcsh:QM1-695 - Abstract
Background Frailty is a geriatric syndrome characterized by increased susceptibility to adverse health outcomes. One major determinant thereof is the gradual weakening of the musculoskeletal system and the associated osteosarcopenia. To improve our understanding of the underlying pathophysiology and, more importantly, to test potential interventions aimed at counteracting frailty, suitable animal models are needed. Methods To evaluate the relevance of prematurely aged PolgA(D257A/D257A) mice as a model for frailty and osteosarcopenia, we quantified the clinical mouse frailty index in PolgA(D257A/D257A) and wild‐type littermates (PolgA(+/+), WT) with age and concertedly assessed the quantity and quality of bone and muscle tissue. Lastly, the anabolic responsiveness of skeletal muscle, muscle progenitors, and bone was assessed. Results PolgA(D257A/D257A) accumulated health deficits at a higher rate compared with WT, resulting in a higher frailty index at 40 and 46 weeks of age (+166%, +278%, P
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- 2020
23. Effects of Early Life Stress on Bone Homeostasis in Mice and Humans
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Würtz-Kozak, Karin, Roszkowski, Martin, Cambria, Elena, Block, Andrea, Kuhn, Gisela A., Abele, Thea, Hitzl, Wolfgang, Drießlein, David, Müller, Ralph, Rapp, Michael A., Mansuy, Isabelle, Peters, Eva M.J., and Wippert, Pia-Maria
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Psychosocial stress ,Bone pathologies ,Osteoporosis ,Bone mineral density ,Childhood ,Neuroendocrine - Abstract
Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies., International Journal of Molecular Sciences, 21 (18), ISSN:1422-0067
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- 2020
24. Hallmarks of Frailty and Osteosarcopenia in Prematurely Aged PolgA (D257A/D257A) Mice
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Scheuren, Ariane, D'Hulst, Gommaar, Kuhn, Gisela, Masschelein, Evi, Wehrle, Esther, De Bock, Katrien, and Müller, Ralph
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Aging ,Osteopenia ,Sarcopenia ,Osteosarcopenia ,mTORC1 ,In vivo micro-CT - Abstract
Background Frailty is a geriatric syndrome characterized by increased susceptibility to adverse health outcomes. One major determinant thereof is the gradual weakening of the musculoskeletal system and the associated osteosarcopenia. To improve our understanding of the underlying pathophysiology and, more importantly, to test potential interventions aimed at counteracting frailty, suitable animal models are needed. Methods To evaluate the relevance of prematurely aged PolgA(D257A/D257A) mice as a model for frailty and osteosarcopenia, we quantified the clinical mouse frailty index in PolgA(D257A/D257A) and wild‐type littermates (PolgA(+/+), WT) with age and concertedly assessed the quantity and quality of bone and muscle tissue. Lastly, the anabolic responsiveness of skeletal muscle, muscle progenitors, and bone was assessed. Results PolgA(D257A/D257A) accumulated health deficits at a higher rate compared with WT, resulting in a higher frailty index at 40 and 46 weeks of age (+166%, +278%, P < 0.0001), respectively, with no differences between genotypes at 34 weeks. Concomitantly, PolgA(D257A/D257A) displayed progressive musculoskeletal deterioration such as reduced bone and muscle mass as well as impaired functionality thereof. In addition to lower muscle weights (−14%, P < 0.05, −23%, P < 0.0001) and fibre area (−20%, P < 0.05, −22%, P < 0.0001) at 40 and 46 weeks, respectively, PolgA(D257A/D257A) showed impairments in grip strength and concentric muscle forces (P < 0.05). PolgA(D257A/D257A) mutation altered the acute response to various anabolic stimuli in skeletal muscle and muscle progenitors. While PolgA(D257A/D257A) muscles were hypersensitive to eccentric contractions as well as leucine administration, shown by larger downstream signalling response of the mechanistic target of rapamycin complex 1, myogenic progenitors cultured in vitro showed severe anabolic resistance to leucine and robust impairments in cell proliferation. Longitudinal micro‐computed tomography analysis of the sixth caudal vertebrae showed that PolgA(D257A/D257A) had lower bone morphometric parameters (e.g. bone volume fraction, trabecular, and cortical thickness, P < 0.05) as well as reduced remodelling activities (e.g. bone formation and resorption rate, P < 0.05) compared with WT. When subjected to 4 weeks of cyclic loading, young but not aged PolgA(D257A/D257A) caudal vertebrae showed load‐induced bone adaptation, suggesting reduced mechanosensitivity with age. Conclusions PolgA(D257A/D257A) mutation leads to hallmarks of age‐related frailty and osteosarcopenia and provides a powerful model to better understand the relationship between frailty and the aging musculoskeletal system. ISSN:2190-5991 ISSN:2190-6009
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- 2020
25. Mechano-Regulation of Trabecular Bone Adaptation Is Controlled by the Local
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Scheuren, Ariane C., Vallaster, Paul, Kuhn, Gisela A., Paul, Graeme R., Malhotra, Angad, Kameo, Yoshitaka, and Müller, Ralph
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Micro-finite element analysis ,Histology ,Bone adaptation ,Mechanical loading ,In vivo micro-CT imaging ,Frequency dependency ,Biomedical Engineering ,Bioengineering and Biotechnology ,Bioengineering ,Original Research ,Biotechnology - Abstract
It is well-established that cyclic, but not static, mechanical loading has anabolic effects on bone. However, the function describing the relationship between the loading frequency and the amount of bone adaptation remains unclear. Using a combined experimental and computational approach, this study aimed to investigate whether trabecular bone mechano-regulation is controlled by mechanical signals in the local in vivo environment and dependent on loading frequency. Specifically, by combining in vivo micro-computed tomography (micro-CT) imaging with micro-finite element (micro-FE) analysis, we monitored the changes in microstructural as well as the mechanical in vivo environment [strain energy density (SED) and SED gradient] of mouse caudal vertebrae over 4 weeks of either cyclic loading at varying frequencies of 2, 5, or 10 Hz, respectively, or static loading. Higher values of SED and SED gradient on the local tissue level led to an increased probability of trabecular bone formation and a decreased probability of trabecular bone resorption. In all loading groups, the SED gradient was superior in the determination of local bone formation and resorption events as compared to SED. Cyclic loading induced positive net (re)modeling rates when compared to sham and static loading, mainly due to an increase in mineralizing surface and a decrease in eroded surface. Consequently, bone volume fraction increased over time in 2, 5, and 10 Hz (+15%, +21% and +24%, p ≤ 0.0001), while static loading led to a decrease in bone volume fraction (−9%, p ≤ 0.001). Furthermore, regression analysis revealed a logarithmic relationship between loading frequency and the net change in bone volume fraction over the 4 week observation period (R2 = 0.74). In conclusion, these results suggest that trabecular bone adaptation is regulated by mechanical signals in the local in vivo environment and furthermore, that mechano-regulation is logarithmically dependent on loading frequency with frequencies below a certain threshold having catabolic effects, and those above anabolic effects. This study thereby provides valuable insights toward a better understanding of the mechanical signals influencing trabecular bone formation and resorption in the local in vivo environment., Frontiers in Bioengineering and Biotechnology, 8, ISSN:2296-4185
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- 2020
26. Effects of long-term in vivo micro-CT imaging on hallmarks of osteopenia and frailty in aging mice
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Scheuren, Ariane C., Kuhn, Gisela A., and Müller, Ralph
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Science ,Medicine - Abstract
In vivo micro-CT has already been used to monitor microstructural changes of bone in mice of different ages and in models of age-related diseases such as osteoporosis. However, as aging is accompanied by frailty and subsequent increased sensitivity to external stimuli such as handling and anesthesia, the extent to which longitudinal imaging can be applied in aging studies remains unclear. Consequently, the potential of monitoring individual mice during the entire aging process-from healthy to frail status-has not yet been exploited. In this study, we assessed the effects of long-term in vivo micro-CT imaging-consisting of 11 imaging sessions over 20 weeks-on hallmarks of aging both on a local (i.e., static and dynamic bone morphometry) and systemic (i.e., frailty index (FI) and body weight) level at various stages of the aging process. Furthermore, using a premature aging model (PolgA(D257A/D257A)), we assessed whether these effects differ between genotypes. The 6th caudal vertebrae of 4 groups of mice (PolgA(D257A/D257A) and PolgA(+/+)) were monitored by in vivo micro-CT every 2 weeks. One group was subjected to 11 scans between weeks 20 and 40 of age, whereas the other groups were subjected to 5 scans between weeks 26-34, 32-40 and 40-46, respectively. The long-term monitoring approach showed small but significant changes in the static bone morphometric parameters compared to the other groups. However, no interaction effect between groups and genotype was found, suggesting that PolgA mutation does not render bone more or less susceptible to long-term micro-CT imaging. The differences between groups observed in the static morphometric parameters were less pronounced in the dynamic morphometric parameters. Moreover, the body weight and FI were not affected by more frequent imaging sessions. Finally, we observed that longitudinal designs including baseline measurements at young adult age are more powerful at detecting effects of in vivo micro-CT imaging on hallmarks of aging than cross-sectional comparisons between multiple groups of aged mice subjected to fewer imaging sessions.
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- 2020
27. Mechanoregulation of cortical bone after implant insertion from Mechanical regulation of bone formation and resorption around implants in a mouse model of osteopenic bone
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Zihui Li, Betts, Duncan, Kuhn, Gisela, Schirmer, Michael, Müller, Ralph, and Ruffoni, Davide
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Figure S1. (a) Changes in cortical thickness (Ct.Th) away from the implantation site in control (CTR) and loaded (CML) mice. # denotes a significant difference (p < 0.05) before and after loading within the same group. * denotes a significant difference (p < 0.05) between groups within the same time point. Data reported as mean value with standard error. (b-e) Frequency distributions of tissue microstrains in formation and resorption regions of cortical bone far from the implant. Data calculated (b) after implant insertion at week-interval (w-i) 1.5 and (c) following 2 weeks of cyclic mechanical loading (w-i 5). Corresponding (re)modeling rules describing the probability of bone formation and bone resorption as a function of the local mechanical stimulation (d) after implant insertion and (e) following 2 weeks of loading. * here denotes a significant difference (p < 0.001) between mean values of strains in formation and resorption surfaces. The full line corresponds to the mean and the shaded area to one standard deviation interval.
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- 2019
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28. Bone architectural parameters. from Mechanical regulation of bone formation and resorption around implants in a mouse model of osteopenic bone
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Zihui Li, Betts, Duncan, Kuhn, Gisela, Schirmer, Michael, Müller, Ralph, and Ruffoni, Davide
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Table S1. Bone architectural parameters at the first (week 0) and the last (week 7) time point for loaded (CML) and control (CTR) mice. The calculated parameters are full tissue volume (TV), full trabecular length along the cranio-caudal axis (Length), trabecular bone volume fraction (BV/TV), trabecular thickness (Tb.Th), cortical thickness (Ct.Th), cortical bone area (Ct.Ar), cortical area fraction (Ct.Ar/Tt.Ar), and cortical porosity (Ct.Po). * p < 0.05 denoted a significant difference between groups for the absolute difference between week 0 and week 7.
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- 2019
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29. Human chondroprogenitors in alginate–collagen hybrid scaffolds produce stable cartilage in vivo
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Studer, Deborah, Cavalli, Emma, Formica, Florian A., Kuhn, Gisela A., Salzmann, Gian, Mumme, Marcus, Steinwachs, Matthias R., Laurent-Applegate, Lee A., Maniura-Weber, Katharina, and Zenobi-Wong, Marcy
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Chondrocytes ,Cartilage regeneration ,Mesenchymal stromal cells ,Chondroprogenitors ,Collagen scaffold ,Allogeneic ,education ,health care economics and organizations ,humanities - Abstract
Journal of Tissue Engineering and Regenerative Medicine, 11 (11), ISSN:1932-6254, ISSN:1932-7005
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- 2017
30. Impaired bone formation in ovariectomized mice reduces implant integration as indicated by longitudinal in vivo micro-computed tomographs
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Li, Zihui, Kuhn, Gisela, Müller, Ralph, and Ruffoni, Davide
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Although osteoporotic bone, with low bone mass and deteriorated bone architecture, provides a less favorable mechanical environment than healthy bone for implant fixation, there is no general agreement on the impact of osteoporosis on peri-implant bone (re)modeling, which is ultimately responsible for the long term stability of the bone-implant system. Here, we inserted an implant in a mouse model mimicking estrogen deficiency-induced bone loss and we monitored with longitudinal in vivo micro-computed tomography the spatio-temporal changes in bone (re)modeling and architecture, considering the separate contributions of trabecular, endocortical and periosteal surfaces. Specifically, 12 week-old C57BL/6J mice underwent OVX/SHM surgery; 9 weeks after we inserted special metal-ceramics implants into the 6th caudal vertebra and we measured bone response with in vivo micro-CT weekly for the following 6 weeks. Our results indicated that ovariectomized mice showed a reduced ability to increase the thickness of the cortical shell close to the implant because of impaired peri-implant bone formation, especially at the periosteal surface. Moreover, we observed that healthy mice had a significantly higher loss of trabecular bone far from the implant than estrogen depleted animals. Such behavior suggests that, in healthy mice, the substantial increase in peri-implant bone formation which rapidly thickened the cortex to secure the implant may raise bone resorption elsewhere and, specifically, in the trabecular network of the same bone but far from the implant. Considering the already deteriorated bone structure of estrogen depleted mice, further bone loss seemed to be hindered. The obtained knowledge on the dynamic response of diseased bone following implant insertion should provide useful guidelines to develop advanced treatments for osteoporotic fracture fixation based on local and selective manipulation of bone turnover in the peri-implant region., PLoS ONE, 12 (9), ISSN:1932-6203
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- 2017
31. Stress and Alterations in Bones: An Interdisciplinary Perspective
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Wippert, Pia-Maria, Rector, Michael, Kuhn, Gisela, and Wuertz-Kozak, Karin
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endocrine pathways ,bone-brain-nervous system interactions ,exercise ,osteoporosis ,biomechanics ,Endocrinology ,Endocrinology, Diabetes and Metabolism ,Mini Review ,bone–brain–nervous system interactions - Abstract
Decades of research have demonstrated that physical stress (PS) stimulates bone remodeling and affects bone structure and function through complex mechanotransduction mechanisms. Recent research has laid ground to the hypothesis that mental stress (MS) also influences bone biology, eventually leading to osteoporosis and increased bone fracture risk. These effects are likely exerted by modulation of hypothalamic-pituitaryadrenal axis activity, resulting in an altered release of growth hormones, glucocorticoids and cytokines, as demonstrated in human and animal studies. Furthermore, molecular cross talk between mental and PS is thought to exist, with either synergistic or preventative effects on bone disease progression depending on the characteristics of the applied stressor. This mini review will explain the emerging concept of MS as an important player in bone adaptation and its potential cross talk with PS by summarizing the current state of knowledge, highlighting newly evolving notions (such as intergenerational transmission of stress and its epigenetic modifications affecting bone) and proposing new research directions., Frontiers in Endocrinology, 8, ISSN:1664-2392
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- 2017
32. Hallmarks of frailty and osteosarcopenia in prematurely aged PolgA(D257A/D257A) mice.
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Scheuren, Ariane C., D'Hulst, Gommaar, Kuhn, Gisela A., Masschelein, Evi, Wehrle, Esther, De Bock, Katrien, and Müller, Ralph
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MUSCLE strength ,BONES ,SKELETAL muscle ,GRIP strength ,CYCLIC loads ,CANCELLOUS bone ,MUSCULOSKELETAL system - Abstract
Background: Frailty is a geriatric syndrome characterized by increased susceptibility to adverse health outcomes. One major determinant thereof is the gradual weakening of the musculoskeletal system and the associated osteosarcopenia. To improve our understanding of the underlying pathophysiology and, more importantly, to test potential interventions aimed at counteracting frailty, suitable animal models are needed. Methods: To evaluate the relevance of prematurely aged PolgA(D257A/D257A) mice as a model for frailty and osteosarcopenia, we quantified the clinical mouse frailty index in PolgA(D257A/D257A) and wild‐type littermates (PolgA(+/+), WT) with age and concertedly assessed the quantity and quality of bone and muscle tissue. Lastly, the anabolic responsiveness of skeletal muscle, muscle progenitors, and bone was assessed. Results: PolgA(D257A/D257A) accumulated health deficits at a higher rate compared with WT, resulting in a higher frailty index at 40 and 46 weeks of age (+166%, +278%, P < 0.0001), respectively, with no differences between genotypes at 34 weeks. Concomitantly, PolgA(D257A/D257A) displayed progressive musculoskeletal deterioration such as reduced bone and muscle mass as well as impaired functionality thereof. In addition to lower muscle weights (−14%, P < 0.05, −23%, P < 0.0001) and fibre area (−20%, P < 0.05, −22%, P < 0.0001) at 40 and 46 weeks, respectively, PolgA(D257A/D257A) showed impairments in grip strength and concentric muscle forces (P < 0.05). PolgA(D257A/D257A) mutation altered the acute response to various anabolic stimuli in skeletal muscle and muscle progenitors. While PolgA(D257A/D257A) muscles were hypersensitive to eccentric contractions as well as leucine administration, shown by larger downstream signalling response of the mechanistic target of rapamycin complex 1, myogenic progenitors cultured in vitro showed severe anabolic resistance to leucine and robust impairments in cell proliferation. Longitudinal micro‐computed tomography analysis of the sixth caudal vertebrae showed that PolgA(D257A/D257A) had lower bone morphometric parameters (e.g. bone volume fraction, trabecular, and cortical thickness, P < 0.05) as well as reduced remodelling activities (e.g. bone formation and resorption rate, P < 0.05) compared with WT. When subjected to 4 weeks of cyclic loading, young but not aged PolgA(D257A/D257A) caudal vertebrae showed load‐induced bone adaptation, suggesting reduced mechanosensitivity with age. Conclusions: PolgA(D257A/D257A) mutation leads to hallmarks of age‐related frailty and osteosarcopenia and provides a powerful model to better understand the relationship between frailty and the aging musculoskeletal system. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
33. Role of HTRA1 in bone formation and regeneration: In vitro and in vivo evaluation
- Author
-
Filliat, Gladys, Mirsaidi, Ali, Tiaden, André N, Kuhn, Gisela A, Weber, Franz E, Oka, Chio, Richards, Peter J; https://orcid.org/0000-0002-1242-7154, Filliat, Gladys, Mirsaidi, Ali, Tiaden, André N, Kuhn, Gisela A, Weber, Franz E, Oka, Chio, and Richards, Peter J; https://orcid.org/0000-0002-1242-7154
- Abstract
The role of mammalian high temperature requirement protease A1 (HTRA1) in somatic stem cell differentiation and mineralized matrix formation remains controversial, having been demonstrated to impart either anti- or pro-osteogenic effects, depending on the in vitro cell model used. The aim of this study was therefore to further evaluate the role of HTRA1 in regulating the differentiation potential and lineage commitment of murine mesenchymal stem cells in vitro, and to assess its influence on bone structure and regeneration in vivo. Our results demonstrated that short hairpin RNA-mediated ablation of Htra1 in the murine mesenchymal cell line C3H10T1/2 increased the expression of several osteogenic gene markers, and significantly enhanced matrix mineralization in response to BMP-2 stimulation. These effects were concomitant with decreases in the expression of chondrogenic gene markers, and increases in adipogenic gene expression and lipid accrual. Despite the profound effects of loss-of-function of HTRA1 on this in vitro osteochondral model, these were not reproduced in vivo, where bone microarchitecture and regeneration in 16-week-old Htra1-knockout mice remained unaltered as compared to wild-type controls. By comparison, analysis of femurs from 52-week-old mice revealed that bone structure was better preserved in Htra1-knockout mice than age-matched wild-type controls. These findings therefore provide additional insights into the role played by HTRA1 in regulating mesenchymal stem cell differentiation, and offer opportunities for improving our understanding of how this multifunctional protease may act to influence bone quality.
- Published
- 2017
34. Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men.
- Author
-
Artsi, Hanna, Gurt, Irina, El-Haj, Madi, Müller, Ralph, Kuhn, Gisela A., Ben Shalom, Gal, Cohen-Kfir, Einav, Abramowitz, Eva, Kandel, Leonid, Safran, Ori, and Dresner-Pollak, Rivka
- Subjects
SIRTUINS ,ADIPOSE tissues ,BONE marrow ,MESENCHYMAL stem cells ,GENE expression ,SCLEROSTIN ,OBESITY - Abstract
Bone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1
Δ/+ ) and wild type (WT) mice. Decreased expression of the thermogenic genes: Prdm16, Pgc1 α , Foxc2, Dio2 , and β 3AR was detected in whole tibiae derived from Sirt1Δ/+ compared to WT female mice. Similarly, decreased expression of Prdm16 and Pgc1 α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from Sirt1Δ/+ compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. In vitro , Sirt1 over-expression in the mesenchymal embryonic fibroblast stem cell line C3HT101/2 increased Pgc1α and Prdm16 protein level. Similarly, pharmacologic activation of Sirt1 by SRT3025 increased Foxc2, Pgc1 α , Dio2, Tfam , and Cyc1 expression while inhibition of Sirt1 by EX527 down-regulated UCP1 in C3HT101/2 cells. Importantly, in human femoral BM-MSCs obtained from female patients undergoing hip operations for fracture or osteoarthritis, Sirt1 activation by SRT3025 increased PGC1 α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated β 3AR, PRDM16 , and UCP1 gene expression, and increased PGC1α protein level. These results show that Sirt1 stimulates a thermogenic gene program in marrow adipocytes in mice and humans via PGC1α activation and sclerostin inhibition. The implications of these findings to bone health, hematopoiesis and whole body energy metabolism remain to be investigated. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
35. Local Mechanical Stimuli Regulate Bone Formation and Resorption in Mice at the Tissue Level
- Author
-
Schulte, Friederike A., Ruffoni, Davide, Lambers, Floor M., Christen, David, Webster, Duncan J., Kuhn, Gisela, and Müller, Ralph
- Subjects
Science ,Image Processing ,Osteopenia and Osteoporosis ,Biomedical Engineering ,Biophysics ,Bioengineering ,Models, Biological ,Bone and Bones ,Weight-Bearing ,Mice ,Engineering ,Osteogenesis ,Biological Systems Engineering ,Animals ,Biomechanics ,Sports and Exercise Medicine ,Bone Resorption ,Biology ,Computerized Simulations ,Physics ,Bone and Joint Mechanics ,Computational Biology ,Metabolic Disorders ,Computer Science ,Signal Processing ,Medicine ,Women's Health ,Biophysic Al Simulations ,Female ,Bone Remodeling ,Stress, Mechanical ,Tomography, X-Ray Computed ,Research Article ,Computer Modeling - Abstract
Bone is able to react to changing mechanical demands by adapting its internal microstructure through bone forming and resorbing cells. This process is called bone modeling and remodeling. It is evident that changes in mechanical demands at the organ level must be interpreted at the tissue level where bone (re)modeling takes place. Although assumed for a long time, the relationship between the locations of bone formation and resorption and the local mechanical environment is still under debate. The lack of suitable imaging modalities for measuring bone formation and resorption in vivo has made it difficult to assess the mechanoregulation of bone three-dimensionally by experiment. Using in vivo micro-computed tomography and high resolution finite element analysis in living mice, we show that bone formation most likely occurs at sites of high local mechanical strain (p, PLoS ONE, 8 (4), ISSN:1932-6203
- Published
- 2013
36. The role of the renal ammonia transporter Rhcg in metabolic responses to dietary protein
- Author
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UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Bounoure, Lisa, Ruffoni, Davide, Muller, Ralph, Kuhn, Gisela A., Bourgeois, Soline, Devuyst, Olivier, Wagner, Carsten A., UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Bounoure, Lisa, Ruffoni, Davide, Muller, Ralph, Kuhn, Gisela A., Bourgeois, Soline, Devuyst, Olivier, and Wagner, Carsten A.
- Abstract
High dietary protein imposes a metabolic acid load requiring excretion and buffering by the kidney. Impaired acid excretion in CKD, with potential metabolic acidosis, may contribute to the progression of CKD. Here, we investigated the renal adaptive response of acid excretory pathways in mice to high-protein diets containing normal or low amounts of acid-producing sulfur amino acids (SAA) and examined how this adaption requires the RhCG ammonia transporter. Diets rich in SAA stimulated expression of enzymes and transporters involved in mediating NH4 (+) reabsorption in the thick ascending limb of the loop of Henle. The SAA-rich diet increased diuresis paralleled by downregulation of aquaporin-2 (AQP2) water channels. The absence of Rhcg transiently reduced NH4 (+) excretion, stimulated the ammoniagenic pathway more strongly, and further enhanced diuresis by exacerbating the downregulation of the Na(+)/K(+)/2Cl(-) cotransporter (NKCC2) and AQP2, with less phosphorylation of AQP2 at serine 256. The high protein acid load affected bone turnover, as indicated by higher Ca(2+) and deoxypyridinoline excretion, phenomena exaggerated in the absence of Rhcg. In animals receiving a high-protein diet with low SAA content, the kidney excreted alkaline urine, with low levels of NH4 (+) and no change in bone metabolism. Thus, the acid load associated with high-protein diets causes a concerted response of various nephron segments to excrete acid, mostly in the form of NH4 (+), that requires Rhcg. Furthermore, bone metabolism is altered by a high-protein acidogenic diet, presumably to buffer the acid load.
- Published
- 2014
37. A novel in vivo vascular imaging approach for hierarchical quantification of vasculature using contrast enhanced micro-computed tomography
- Author
-
Nebuloni, Laura, Kuhn, Gisela A, Vogel, Johannes, Müller, Ralph, Nebuloni, Laura, Kuhn, Gisela A, Vogel, Johannes, and Müller, Ralph
- Abstract
The vasculature of body tissues is continuously subject to remodeling processes originating at the micro-vascular level. The formation of new blood vessels (angiogenesis) is essential for a number of physiological and pathophysiological processes such as tissue regeneration, tumor development and the integration of artificial tissues. There are currently no time-lapsed in vivo imaging techniques providing information on the vascular network at the capillary level in a non-destructive, three-dimensional and high-resolution fashion. This paper presents a novel imaging framework based on contrast enhanced micro-computed tomography (micro-CT) for hierarchical in vivo quantification of blood vessels in mice, ranging from largest to smallest structures. The framework combines for the first time a standard morphometric approach with densitometric analysis. Validation tests showed that the method is precise and robust. Furthermore, the framework is sensitive in detecting different perfusion levels after the implementation of a murine ischemia-reperfusion model. Correlation with both histological data and micro-CT analysis of vascular corrosion casts confirmed accuracy of the method. The newly developed time-lapsed imaging approach shows high potential for in vivo monitoring of a number of different physiological and pathological conditions in angiogenesis and vascular development.
- Published
- 2014
38. PLGA/PEG-hydrogel composite scaffolds with controllable mechanical properties
- Author
-
Rahman, Cheryl V., Kuhn, Gisela, White, Lisa J., Kirby, Giles T. S., Varghese, Oommen P., McLaren, Jane S., Cox, Helen C., Rose, Felicity R. A. J., Mueller, Ralph, Hilborn, Jöns, Shakesheff, Kevin M., Rahman, Cheryl V., Kuhn, Gisela, White, Lisa J., Kirby, Giles T. S., Varghese, Oommen P., McLaren, Jane S., Cox, Helen C., Rose, Felicity R. A. J., Mueller, Ralph, Hilborn, Jöns, and Shakesheff, Kevin M.
- Abstract
Biodegradable polymer scaffolds have great potential for regenerative medicine applications such as the repair of musculoskeletal tissues. Here, we describe the development of scaffolds that blend hydrogel components with thermoplastic materials, combining the unique properties of both components to create mouldable formulations. This study focuses on the structural and mechanical properties of the composite scaffolds, produced by combining temperature-sensitive poly(DL-lactic acid-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) particles with a hydrogel component [Pluronic F127, fibrin or hyaluronic acid (HyA)]. The composite formulations solidified over time at 37 degrees C, with a significant increase (p 0.05) in compressive strength observed from 15 min to 2 h at this temperature. The maximum compressive strength was 1.2 MPa for PLGA/PEG-Pluronic F127 scaffolds, 2.4 MPa for PLGA/PEG-HyA scaffolds and 0.6 MPa for PLGA/PEG-fibrin scaffolds. Porosity for each of the PLGA/PEG-hydrogel formulations tested was between 50 and 51%. This study illustrates the ability to combine this thermoplastic PLGA/PEG system with hydrogels to fabricate composite scaffolds, and demonstrates that altering the particle to hydrogel ratio produces scaffolds with varying mechanical properties.
- Published
- 2013
- Full Text
- View/download PDF
39. Engineering the Growth Factor Microenvironment with Fibronectin Domains to Promote Wound and Bone Tissue Healing
- Author
-
Martino, Mikael M., Tortelli, Federico, Mochizuki, Mayumi, Traub, Stephanie, Ben-David, Dror, Kuhn, Gisela A., Mueller, Ralph, Livne, Erella, Eming, Sabine A., Hubbell, Jeffrey A., Martino, Mikael M., Tortelli, Federico, Mochizuki, Mayumi, Traub, Stephanie, Ben-David, Dror, Kuhn, Gisela A., Mueller, Ralph, Livne, Erella, Eming, Sabine A., and Hubbell, Jeffrey A.
- Abstract
Although growth factors naturally exert their morphogenetic influences within the context of the extracellular matrix microenvironment, the interactions among growth factors, their receptors, and other extracellular matrix components are typically ignored in clinical delivery of growth factors. We present an approach for engineering the cellular microenvironment to greatly accentuate the effects of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) for skin repair, and of bone morphogenetic protein-2 (BMP-2) and PDGF-BB for bone repair. A multifunctional recombinant fragment of fibronectin (FN) was engineered to comprise (i) a factor XIIIa substrate fibrin-binding sequence, (ii) the 9th to 10th type III FN repeat (FN III9-10) containing the major integrin-binding domain, and (iii) the 12th to 14th type III FN repeat (FN III12-14), which binds growth factors promiscuously, including VEGF-A165, PDGF-BB, and BMP-2. We show potent synergistic signaling and morphogenesis between alpha(5)beta(1) integrin and the growth factor receptors, but only when FN III9-10 and FN III12-14 are proximally presented in the same polypeptide chain (FN III9-10/12-14). The multifunctional FN III9-10/12-14 greatly enhanced the regenerative effects of the growth factors in vivo in a diabetic mouse model of chronic wounds (primarily through an angiogenic mechanism) and in a rat model of critical-size bone defects (through a mesenchymal stem cell recruitment mechanism) at doses where the growth factors delivered within fibrin only had no significant effects.
- Published
- 2011
40. A Novel In Vivo Vascular Imaging Approach for Hierarchical Quantification of Vasculature Using Contrast Enhanced Micro-Computed Tomography.
- Author
-
Nebuloni, Laura, Kuhn, Gisela A., Vogel, Johannes, and Müller, Ralph
- Subjects
- *
BLOOD vessels , *MEDICAL imaging systems , *COMPUTED tomography , *BIOENGINEERING , *BIOMEDICAL engineering , *LABORATORY mice - Abstract
The vasculature of body tissues is continuously subject to remodeling processes originating at the micro-vascular level. The formation of new blood vessels (angiogenesis) is essential for a number of physiological and pathophysiological processes such as tissue regeneration, tumor development and the integration of artificial tissues. There are currently no time-lapsed in vivo imaging techniques providing information on the vascular network at the capillary level in a non-destructive, three-dimensional and high-resolution fashion. This paper presents a novel imaging framework based on contrast enhanced micro-computed tomography (micro-CT) for hierarchical in vivo quantification of blood vessels in mice, ranging from largest to smallest structures. The framework combines for the first time a standard morphometric approach with densitometric analysis. Validation tests showed that the method is precise and robust. Furthermore, the framework is sensitive in detecting different perfusion levels after the implementation of a murine ischemia-reperfusion model. Correlation with both histological data and micro-CT analysis of vascular corrosion casts confirmed accuracy of the method. The newly developed time-lapsed imaging approach shows high potential for in vivo monitoring of a number of different physiological and pathological conditions in angiogenesis and vascular development. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
41. Lentiviral-Mediated Integrin α5 Expression in Human Adult Mesenchymal Stromal Cells Promotes Bone Repair in Mouse Cranial and Long-Bone Defects.
- Author
-
Srouji, Samer, Ben-David, Dror, Fromigué, Olivia, Vaudin, Pascal, Kuhn, Gisela, Müller, Ralph, Livne, Erella, and Marie, Pierre J.
- Published
- 2012
- Full Text
- View/download PDF
42. The flavonol quercetin activates basolateral K[sup+] channels in rat distal colon epithelium.
- Author
-
Cermak, Rainer, Kuhn, Gisela, and Wolffram, Siegfried
- Subjects
- *
QUERCETIN , *COLON (Anatomy) , *RAT physiology - Abstract
1 The flavonol quercetin has been shown to activate a Cl[sup -] secretion in rat colon. Unlike the secretory activity of the related isoflavone genistein, quercetin's secretory activity does not depend on cyclic AMP; instead, it depends on Ca[sup 2+]. We investigated the possible involvement of Ca[sup 2+] dependent basolateral K[sup +] channels using apically permeabilized rat distal colon epithelium mounted in Ussing chambers. 2 In intact epithelium, quercetin induced an increase in short-circuit current (I[sub sc]), which was diminished by the Cl[sup -] channel blockers NPPB and DPC, but not by glibenclamide, DIDS or anthracene-9-carboxylic acid. The effect of the flavonol was also inhibited by several serosally applied K[sup +] channel blockers (Ba[sup 2+], quinine, clotrimazole, tetrapentylammonium, 293B), whereas other K[sup +] channel blockers failed to influence the quercetin-induced increase in I[sub sc] (tetraethylammonium, charybdotoxin). 3 The apical membrane was permeabilized by mucosal addition of nystatin and a serosally directed K[sup +] gradient was applied. The successful permeabilization was confirmed by experiments demonstrating the failure of bumetanide to inhibit the carbachol-induced current. 4 In apically permeabilized epithelium, quercetin induced a K[sup +] current (I[sub K]), which was neither influenced by ouabain nor by bumetanide. Whereas DPC, NPPB, charybdotoxin and 293B failed to inhibit this I[sub K], quinine, Ba[sup 2+], clotrimazole and tetrapentylammonium were effective blockers of this current. 5 We conclude from these results that at least part of the quercetin-induced Cl[sup -] secretion can be explained by an activation of basolateral K[sup +] channels. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
43. Abortion in Mice with Excessive Erythrocytosis Is Due to Impaired Arteriogenesis of the Uterine Arcade1
- Author
-
Gassmann, Max, Manini, Annamaria, Stallmach, Thomas, Saam, Bianca, Kuhn, Gisela, Grenacher, Beat, Bogdanova, Anna Y., and Vogel, Johannes
- Abstract
We postulate that repeated pregnancy loss, intrauterine growth restriction, and preeclampsia are caused by impaired elevation of uterine blood flow due to disturbed arteriogenesis of the uterine arcade. This hypothesis is based on the observation that pregnant human erythropoietin-overexpressing (plasma levels elevated 12-fold) mice (termed tg6 mice) suffering from excessive erythrocytosis generally abort at midgestation unless their hematocrit of 0.85 is drastically lowered. Transgenic mice show placental malformations that parallel those observed in pregnant women suffering from impaired uterine perfusion. Shear stress, a key factor inducing arteriogenesis, was 5-fold lower in tg6 mice compared with wildtype (WT) littermates. Consequently, uterine artery growth was reduced, and dramatically fewer viable pups (1.63 ± 2.20 vs. 8.10 ± 0.74 in WT) of lower weight (1.29 ± 0.07 g vs. 1.62 ± 0.12 g in WT) were delivered in first pregnancies. Only in subsequent pregnancies did tg6 deliver approximately the expected number of pups. Birth weights of tg6 offspring, however, remained reduced. As the spleen is a major site of extramedullary erythropoiesis in tg6 animals, splenectomy reduced the hematocrit to 0.6–0.7. In turn, shear stress increased to normal values, and splenectomized primiparous tg6 showed normal uterine artery growth and delivery of pups similar in number and weight compared with WT. We conclude that poor arteriogenesis is a previously unappreciated cause for clinically important pregnancy complications.
- Published
- 2008
- Full Text
- View/download PDF
44. Effects of Early Life Stress on Bone Homeostasis in Mice and Humans.
- Author
-
Wuertz-Kozak, Karin, Roszkowski, Martin, Cambria, Elena, Block, Andrea, Kuhn, Gisela A., Abele, Thea, Hitzl, Wolfgang, Drießlein, David, Müller, Ralph, Rapp, Michael A., Mansuy, Isabelle M., Peters, Eva M. J., and Wippert, Pia M.
- Subjects
BONES ,BONE density ,LIFE change events ,REGULATION of body weight ,BONE diseases ,BONE resorption - Abstract
Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
45. Habitual loading measured in individual mice one week post surgery predicts fracture callus stiffness progression in a femur defect model
- Author
-
Paul, Graeme R., Wehrle, Esther, Zhang, Jianhua, Kuhn, Gisela A., and Müller, Ralph
- Published
- 2020
- Full Text
- View/download PDF
46. Effects of long-term in vivo micro-CT imaging on hallmarks of osteopenia and frailty in aging mice
- Author
-
Scheuren, Ariane C., Kuhn, Gisela A., and Müller, Ralph
- Subjects
3. Good health - Abstract
PLoS ONE, 15 (9), ISSN:1932-6203
47. A Novel In Vivo Vascular Imaging Approach for Hierarchical Quantification of Vasculature Using Contrast Enhanced Micro-Computed Tomography
- Author
-
Nebuloni, Laura, Kuhn, Gisela A., Vogel, Johannes, and Müller, Ralph
- Subjects
3. Good health - Abstract
The vasculature of body tissues is continuously subject to remodeling processes originating at the micro-vascular level. The formation of new blood vessels (angiogenesis) is essential for a number of physiological and pathophysiological processes such as tissue regeneration, tumor development and the integration of artificial tissues. There are currently no time-lapsed in vivo imaging techniques providing information on the vascular network at the capillary level in a non-destructive, three-dimensional and high-resolution fashion. This paper presents a novel imaging framework based on contrast enhanced micro-computed tomography (micro-CT) for hierarchical in vivo quantification of blood vessels in mice, ranging from largest to smallest structures. The framework combines for the first time a standard morphometric approach with densitometric analysis. Validation tests showed that the method is precise and robust. Furthermore, the framework is sensitive in detecting different perfusion levels after the implementation of a murine ischemia-reperfusion model. Correlation with both histological data and micro-CT analysis of vascular corrosion casts confirmed accuracy of the method. The newly developed time-lapsed imaging approach shows high potential for in vivo monitoring of a number of different physiological and pathological conditions in angiogenesis and vascular development., PLoS ONE, 9 (1), ISSN:1932-6203
48. Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis
- Author
-
Lambers, Floor, Kuhn, Gisela, Schulte, Friederike, Koch, Kathleen, Müller, Ralph, Lambers, Floor, Kuhn, Gisela, Schulte, Friederike, Koch, Kathleen, and Müller, Ralph
- Abstract
Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (μCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6mice were ovariectomized (OVX, n=11) or sham-operated (SHM, n=9) and monitored with in vivo μCT on the day of surgery and every 2weeks after, up to 12weeks. There was a significant decrease in bone volume fraction for OVX (−35%) compared to SHM (+16%) in trabecular bone (P<0.001). For OVX, high-turnover bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P<0.001). Furthermore there was a significant decrease in whole-bone stiffness for OVX (−16%) compared to SHM (+11%, P<0.001). From these results we conclude that the mouse tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P<0.001) and a delayed increase in bone formation rate (P<0.001). Monitoring transient bone biology is a promising method for future research
49. Mechanical regulation of bone formation and resorption around implants in a mouse model of osteopenic bone
- Author
-
Li, Zihui, Betts, Duncan, Kuhn, Gisela, Schirmer, Michael, Müller, Ralph, and Ruffoni, Davide
- Published
- 2019
- Full Text
- View/download PDF
50. Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration.
- Author
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Martino, Mikaël M., Maruyama, Kenta, Kuhn, Gisela A., Satoh, Takashi, Takeuchi, Osamu, Müller, Ralph, and Akira, Shizuo
- Published
- 2016
- Full Text
- View/download PDF
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