scholarly journals Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Cori N. Booker ◽  
Christopher L. Haga ◽  
Siddaraju V. Boregowda ◽  
Jacqueline Strivelli ◽  
Donald G. Phinney
Keyword(s):  
Bone Loss ◽  
Progenitor Cells ◽  
Structural Changes ◽  
Weight Bearing ◽  
Hindlimb Unloading ◽  
Integrative Approach ◽  
Transcriptional Responses ◽  
Time Resolved ◽  
Mechanical Unloading ◽  
Transcript Profiles

AbstractDisuse osteoporosis (DO) results from mechanical unloading of weight-bearing bones and causes structural changes that compromise skeletal integrity, leading to increased fracture risk. Although bone loss in DO results from imbalances in osteoblast vs. osteoclast activity, its effects on skeletal stem/progenitor cells (SSCs) is indeterminate. We modeled DO in mice by 8 and 14 weeks of hindlimb unloading (HU) or 8 weeks of unloading followed by 8 weeks of recovery (HUR) and monitored impacts on animal physiology and behavior, metabolism, marrow adipose tissue (MAT) volume, bone density and micro-architecture, and bone marrow (BM) leptin and tyrosine hydroxylase (TH) protein expression, and correlated multi-systems impacts of HU and HUR with the transcript profiles of Lin−LEPR+ SSCs and mesenchymal stem cells (MSCs) purified from BM. Using this integrative approach, we demonstrate that prolonged HU induces muscle atrophy, progressive bone loss, and MAT accumulation that paralleled increases in BM but not systemic leptin levels, which remained low in lipodystrophic HU mice. HU also induced SSC quiescence and downregulated bone anabolic and neurogenic pathways, which paralleled increases in BM TH expression, but had minimal impacts on MSCs, indicating a lack of HU memory in culture-expanded populations. Although most impacts of HU were reversed by HUR, trabecular micro-architecture remained compromised and time-resolved changes in the SSC transcriptome identified various signaling pathways implicated in bone formation that were unresponsive to HUR. These findings indicate that HU-induced alterations to the SSC transcriptome that persist after reloading may contribute to poor bone recovery.

scholarly journals Author Correction: Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Cori N. Booker ◽  
Christopher L. Haga ◽  
Siddaraju V. Boregowda ◽  
Jacqueline Strivelli ◽  
Donald G. Phinney
Keyword(s):  
Progenitor Cells ◽  
Hindlimb Unloading ◽  
Transcriptional Responses

Daily Acute Bouts of Weight-bearing During Hindlimb Unloading Mitigate Disuse-Induced Deficits in Cancellous Bone

2020 ◽  
Vol 6 (2) ◽  
pp. 2-11 ◽  
Author(s):  
Rihana S. Bokhari ◽  
Corinne E. Metzger ◽  
Matthew R. Allen ◽  
Susan A. Bloomfield
Keyword(s):  
Bone Loss ◽  
Cancellous Bone ◽  
Weight Bearing ◽  
Space Station ◽  
Hindlimb Unloading ◽  
Mineral Density ◽  
Normal Loading ◽  
Bone Mineral Density Loss ◽  
Total Body Mass ◽  
Total Body

AbstractInternational Space Station crewmembers experience microgravity, resulting in musculoskeletal losses. It remains unclear how much mechanical loading during disuse is sufficient to mitigate disuse-induced bone loss. We examined 75 minutes of weight-bearing per day on disuse-induced bone loss during hindlimb unloading (HU). Female C57BL/6J mice, 17 weeks (n=10/group), were exposed to HU for 28 days or were ambulatory controls (CC). Half of the HU animals were continuously unloaded while the remainder were removed from tail suspension for ~75 min/day for cage activity weight-bearing (HU+WB). HU and HU+WB led to total body mass and bone mineral density loss. HU+WB mitigated HU-induced losses in total body fat and lean mass and, in the distal femur, prevented losses in μCT measures of cancellous bone volume and microarchitecture. These findings support the robust impact of short durations of normal loading on preventing or mitigating HU-induced bone loss.

scholarly journals Simulated spaceflight produces a rapid and sustained loss of osteoprogenitors and an acute but transitory rise of osteoclast precursors in two genetic strains of mice

2012 ◽  
Vol 303 (11) ◽  
pp. E1354-E1362 ◽  
Author(s):  
Mohammad Shahnazari ◽  
Pam Kurimoto ◽  
Benjamin M. Boudignon ◽  
Benjamin E. Orwoll ◽  
Daniel D. Bikle ◽  
...  
Keyword(s):  
Bone Loss ◽  
Cancellous Bone ◽  
Bone Structure ◽  
Bone Cells ◽  
Weight Bearing ◽  
Bone Adaptation ◽  
Hindlimb Unloading ◽  
Skeletal Unloading ◽  
Precursor Pool ◽  
Cancellous Bone Structure

Loss of skeletal weight bearing or skeletal unloading as occurs during spaceflight inhibits bone formation and stimulates bone resorption. These are associated with a decline in the osteoblast (Ob.S/BS) and an increase in the osteoclast (Oc.S/BS) bone surfaces. To determine the temporal relationship between changes in the bone cells and their marrow precursor pools during sustained unloading, and whether genetic background influences these relationships, we used the hindlimb unloading model to induce bone loss in two strains of mice known to respond to load and having significantly different cancellous bone volumes (C57BL/6 and DBA/2 male mice). Skeletal unloading caused a progressive decline in bone volume that was accompanied by strain-specific changes in Ob.S/BS and Oc.S/BS. These were associated with a sustained reduction in the osteoprogenitor population and a dramatic but transient increase in the osteoclast precursor pool size in both strains. The results reveal that bone adaptation to skeletal unloading involves similar rapid changes in the osteoblast and osteoclast progenitor populations in both strains of mice but striking differences in Oc.S/BS dynamics, BFR, and cancellous bone structure. These strain-specific differences suggest that genetics plays an important role in determining the osteoblast and osteoclast populations on the bone surface and the dynamics of bone loss in response to skeletal unloading.

scholarly journals The Skeletal Cellular and Molecular Underpinning of the Murine Hindlimb Unloading Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Priyanka Garg ◽  
Maura Strigini ◽  
Laura Peurière ◽  
Laurence Vico ◽  
Donata Iandolo
Keyword(s):  
Bone Loss ◽  
Mechanical Loading ◽  
Weight Bearing ◽  
Bone Adaptation ◽  
Hindlimb Unloading ◽  
Molecular Pathways ◽  
Long Bones ◽  
Confounding Factors ◽  
Environmental Temperatures

Bone adaptation to spaceflight results in bone loss at weight bearing sites following the absence of the stimulus represented by ground force. The rodent hindlimb unloading model was designed to mimic the loss of mechanical loading experienced by astronauts in spaceflight to better understand the mechanisms causing this disuse-induced bone loss. The model has also been largely adopted to study disuse osteopenia and therefore to test drugs for its treatment. Loss of trabecular and cortical bone is observed in long bones of hindlimbs in tail-suspended rodents. Over the years, osteocytes have been shown to play a key role in sensing mechanical stress/stimulus via the ECM-integrin-cytoskeletal axis and to respond to it by regulating different cytokines such as SOST and RANKL. Colder experimental environments (~20–22°C) below thermoneutral temperatures (~28–32°C) exacerbate bone loss. Hence, it is important to consider the role of environmental temperatures on the experimental outcomes. We provide insights into the cellular and molecular pathways that have been shown to play a role in the hindlimb unloading and recommendations to minimize the effects of conditions that we refer to as confounding factors.

Solvent Dependence of Structural Dynamics and Spin-flip Processes in 3,4,5-tri(9H-carbazole-9-yl)benzonitrile (ortho-3CzBN)

2020 ◽  
Author(s):  
Masaki Saigo ◽  
Kiyoshi Miyata ◽  
Hajime Nakanotani ◽  
Chihaya Adachi ◽  
Ken Onda
Keyword(s):  
Dft Calculations ◽  
Excited States ◽  
Structural Changes ◽  
Photophysical Properties ◽  
Delayed Fluorescence ◽  
Time Resolved ◽  
Thermally Activated Delayed Fluorescence ◽  
Thermally Activated ◽  
Solvent Dependence ◽  
Acetonitrile Solutions

We have investigated the solvent-dependence of structural changes along with intersystem crossing of a thermally activated delayed fluorescence (TADF) molecule, 3,4,5-tri(9H-carbazole-9-yl)benzonitrile (o-3CzBN), in toluene, tetrahydrofuran, and acetonitrile solutions using time-resolved infrared (TR-IR) spectroscopy and DFT calculations. We found that the geometries of the S1 and T1 states are very similar in all solvents though the photophysical properties mostly depend on the solvent. In addition, the time-dependent DFT calculations based on these geometries suggested that the thermally activated delayed fluorescence process of o-3CzBN is governed more by the higher-lying excited states than by the structural changes in the excited states.<br>

scholarly journals Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lei Qin ◽  
Xuekun Fu ◽  
Jing Ma ◽  
Manxia Lin ◽  
Peijun Zhang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mechanical Stimulation ◽  
Fluid Shear Stress ◽  
Weight Bearing ◽  
Underlying Mechanism ◽  
Long Bones ◽  
Cell Orientation ◽  
Cytoskeleton Organization

AbstractOsteocytes act as mechanosensors in bone; however, the underlying mechanism remains poorly understood. Here we report that deleting Kindlin-2 in osteocytes causes severe osteopenia and mechanical property defects in weight-bearing long bones, but not in non-weight-bearing calvariae. Kindlin-2 loss in osteocytes impairs skeletal responses to mechanical stimulation in long bones. Control and cKO mice display similar bone loss induced by unloading. However, unlike control mice, cKO mice fail to restore lost bone after reloading. Osteocyte Kindlin-2 deletion impairs focal adhesion (FA) formation, cytoskeleton organization and cell orientation in vitro and in bone. Fluid shear stress dose-dependently increases Kindlin-2 expression and decreases that of Sclerostin by downregulating Smad2/3 in osteocytes; this latter response is abolished by Kindlin-2 ablation. Kindlin-2-deficient osteocytes express abundant Sclerostin, contributing to bone loss in cKO mice. Collectively, we demonstrate an indispensable novel role of Kindlin-2 in maintaining skeletal responses to mechanical stimulation by inhibiting Sclerostin expression during osteocyte mechanotransduction.

Anti-RANKL monoclonal antibody and bortezomib prevent mechanical unloading-induced bone loss

2021 ◽  
Author(s):  
Yi Ding ◽  
Yu Cui ◽  
Xi Yang ◽  
Xiaolu Wang ◽  
Guangzhao Tian ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Loss ◽  
Mechanical Unloading

scholarly journals Selective time-dependent changes of Cu(DPPE)(DMP)·PF6on photoexcitation

2014 ◽  
Vol 70 (a1) ◽  
pp. C776-C776 ◽  
Author(s):  
Elzbieta Trzop ◽  
Bertrand Fournier ◽  
Katarzyna Jarzembska ◽  
Jesse Sokolow ◽  
Radoslaw Kaminski ◽  
...  
Keyword(s):  
Structural Changes ◽  
Dye Sensitized Solar Cells ◽  
Department Of Energy ◽  
Data Sets ◽  
Monoclinic System ◽  
Time Resolved ◽  
Pump Probe ◽  
Light Emitting Devices ◽  
Potential Applications ◽  
Photon Source

Thanks to their potential applications as light-emitting devices, chemical sensors and dye-sensitized solar cells, heteroleptic copper (I) complexes have been extensively studied. Cu(DPPE)(DMP)·PF6(dppe= 1,2-bis(diphenylphosphino)ethane; dmp = 2,9-dimethyl-1,10-phenanthroline) crystallizes in the monoclinic system, P21/c, with two independent molecules in the asymmetric unit. Previous studies on this system [1,2] show strong temperature-dependent emission. The complex was studied at 90K under 355nm laser excitation. At this temperature, the luminescence decay for Cu(DPPE)(DMP)·PF6is biexponential with lifetimes of ~3μs and ~28μs. Two time-resolved X-ray diffraction techniques were applied for studies: (1) a Laue technique at BioCARS ID-14 beamline at the Advanced Photon Source, and (2) monochromatic diffraction at a newly constructed in-house pump-probe monochromatic facility at the University at Buffalo. Structural changes determined with the two methods are in qualitative agreement; discrepancies in position of the Cu and P atoms were observed. The molecular distortions were smaller than those determined at 16K in the earlier synchrotron study by Vorontsov et al. [2]. Photodeformation maps (see Figure below), in which the increase in temperature on photoexcitation has been eliminated, clearly illustrate the photoinduced atomic shifts for both data sets. Results will be compared with those obtained for other studied heteroleptic copper (I) complexes, for instance Cu[(1,10-phenanthroline-N,N′) bis(triphenylphosphine)]·BF4[3]. The in-house pump-probe facility is discussed by Radoslaw Kaminski at this meeting. Research funded by the National Science Foundation (CHE1213223). BioCARS Sector 14 at APS is supported by NIH (RR007707). The Advanced Photon Source is funded by the Office of Basic Energy Sciences, U.S. Department of Energy, (W-31-109-ENG-38). KNJ is supported by the Polish Ministry of Science and Higher Education through the "Mobility Plus" program.

Metaphase-Based Cytogenetic Approach Identifies Radiation-Induced Chromosome and Chromatid Aberrations in Zebrafish Embryos

2021 ◽  
Author(s):  
Halida Thanveer Asana Marican ◽  
Hongyuan Shen
Keyword(s):  
Animal Model ◽  
Radiation Exposure ◽  
Progenitor Cells ◽  
Chromosome Aberrations ◽  
Structural Changes ◽  
Current Knowledge ◽  
Living Organism ◽  
Zebrafish Embryos ◽  
Radiation Induced

Metaphase-based cytogenetic methods based on scoring of chromosome aberrations for the estimation of the radiation dose received provide a powerful approach for evaluating the associated risk upon radiation exposure and form the bulk of our current knowledge of radiation-induced chromosome damages. They mainly rely on inducing quiescent peripheral lymphocytes into proliferation and blocking them at metaphases to quantify the damages at the chromosome level. However, human organs and tissues demonstrate various sensitivity towards radiation and within them, self-proliferating progenitor/stem cells are believed to be the most sensitive populations. The radiation-induced chromosome aberrations in these cells remain largely unknown, especially in the context of an intact living organism. Zebrafish is an ideal animal model for research into this aspect due to their small size and the large quantities of progenitor cells present during the embryonic stages. In this study, we employ a novel metaphase-based cytogenetic approach on zebrafish embryos and demonstrate that chromosome-type and chromatid-type aberrations could be identified in progenitor cells at different cell-cycle stages at the point of radiation exposure. Our work positions zebrafish at the forefront as a useful animal model for studying radiation-induced chromosome structural changes in vivo.

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