Physiological levels of estradiol limit murine osteoarthritis progression

Among patients with knee osteoarthritis (OA), postmenopausal women are overrepresented. The purpose of this study was to determine whether deficiency of female sex steroids affects OA progression and to evaluate the protective effect of treatment with a physiological dose of 17β-estradiol (E2) on OA progression using a murine model. Ovariectomy (OVX) of female mice was used to mimic a postmenopausal state. OVX or sham-operated mice underwent surgery for destabilization of the medial meniscus (DMM) to induce OA. E2 was administered in a pulsed manner for 2 and 8 weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density (BMD) decreased after OVX compared with sham-operated mice at 8 weeks post-DMM surgery. Additionally, OVX mice displayed decreased motor activity, reduced threshold of pain sensitivity, and increased number of T cells in the inguinal lymph nodes compared to sham-operated mice 2 weeks after OA induction. Eight weeks of treatment with E2 prevented cartilage damage and thickening of the synovium in OVX OA mice. The motor activity was improved after E2 replacement at the 2 weeks time point, which was also associated with lower pain sensitivity in the OA paw. E2 treatment protected against OVX-induced loss of subchondral trabecular bone. The number of T cells in the inguinal lymph nodes was reduced by E2 treatment after 8 weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms. © 2022 The authors Published by Bioscientifica Ltd.</p

Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2

Estrogen receptor‐α (ERα) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERα domains for the osteogenic response to mechanical loading, gene‐targeted mouse models with (1) a complete ERα inactivation (ERα−/−), (2) specific inactivation of activation function 1 (AF‐1) in ERα (ERαAF‐10), or (3) specific inactivation of ERαAF‐2 (ERαAF‐20) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ERα−/− mice displayed a severely reduced osteogenic response to loading with changes in cortical area (−78% ± 15%, p < 0.01) and periosteal BFR (−81% ± 9%, p < 0.01) being significantly lower than in wild‐type (WT) mice. ERαAF‐10 mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area −40% ± 11%, p < 0.05 and periosteal BFR −41% ± 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ERαAF‐20 mice. Mechanical loading of transgenic estrogen response element (ERE)‐luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE‐mediated pathways. In conclusion, ERα is required for the osteogenic response to mechanical loading in a ligand‐independent manner involving AF‐1 but not AF‐2

First Measurement of Hard Exclusive π- Δ++ Electroproduction Beam-Spin Asymmetries off the Proton

The polarized cross-section ratio σLT′/σ0 from hard exclusive π-Δ++ electroproduction off an unpolarized hydrogen target has been extracted based on beam-spin asymmetry measurements using a 10.2 GeV/10.6 GeV incident electron beam and the CLAS12 spectrometer at Jefferson Lab. The study, which provides the first observation of this channel in the deep-inelastic regime, focuses on very forward-pion kinematics in the valence regime, and photon virtualities ranging from 1.5 GeV2 up to 7 GeV2. The reaction provides a novel access to the d-quark content of the nucleon and to p→Δ++ transition generalized parton distributions. A comparison to existing results for hard exclusive π+n and π0p electroproduction is provided, which shows a clear impact of the excitation mechanism, encoded in transition generalized parton distributions, on the asymmetry

Observation of Azimuth-Dependent Suppression of Hadron Pairs in Electron Scattering Off Nuclei

We present the first measurement of dihadron angular correlations in electron-nucleus scattering. The data were taken with the CLAS detector and a 5.0 GeV electron beam incident on deuterium, carbon, iron, and lead targets. Relative to deuterium, the nuclear yields of charged-pion pairs show a strong suppression for azimuthally opposite pairs, no suppression for azimuthally nearby pairs, and an enhancement of pairs with large invariant mass. These effects grow with increased nuclear size. The data are qualitatively described by the gibuu model, which suggests that hadrons form near the nuclear surface and undergo multiple scattering in nuclei. These results show that angular correlation studies can open a new way to elucidate how hadrons form and interact inside nuclei

Observation of azimuth-dependent suppression of hadron pairs in electron scattering off nuclei

We present the first measurement of di-hadron angular correlations in electron-nucleus scattering. The data were taken with the CLAS detector and a 5.0 GeV electron beam incident on deuterium, carbon, iron, and lead targets. Relative to deuterium, the nuclear yields of charged-pion pairs show a strong suppression for azimuthally opposite pairs, no suppression for azimuthally nearby pairs, and an enhancement of pairs with large invariant mass. These effects grow with increased nuclear size. The data are qualitatively described by the GiBUU model, which suggests that hadrons form near the nuclear surface and undergo multiple-scattering in nuclei. These results show that angular correlation studies can open a new way to elucidate how hadrons form and interact inside nucleiComment: 6 pages, 4 figure

First Measurement of Λ\Lambda Electroproduction off Nuclei in the Current and Target Fragmentation Regions

We report results of $\Lambda$ hyperon production in semi-inclusive deep-inelastic scattering off deuterium, carbon, iron, and lead targets obtained with the CLAS detector and the Continuous Electron Beam Accelerator Facility 5.014~GeV electron beam. These results represent the first measurements of the $\Lambda$ multiplicity ratio and transverse momentum broadening as a function of the energy fraction~($z$) in the current and target fragmentation regions. The multiplicity ratio exhibits a strong suppression at high~$z$~and~an enhancement at~low~$z$. The measured transverse momentum broadening is an order of magnitude greater than that seen for light mesons. This indicates that the propagating entity interacts very strongly with the nuclear medium, which suggests that propagation of diquark configurations in the nuclear medium takes place at least part of the time, even at high~$z$. The trends of these results are qualitatively described by the Giessen Boltzmann-Uehling-Uhlenbeck transport model, particularly for the multiplicity ratios. These observations will potentially open a new era of studies of the structure of the nucleon as well as of strange baryons.Comment: 14 pages, 6 figure

Arthritis Res Ther

INTRODUCTION: Estrogen (E2) delays onset and decreases severity of experimental arthritis. The aim of this study was to investigate the importance of total estrogen receptor alpha (ERalpha) expression and cartilage-specific ERalpha expression in genetically modified mice for the ameliorating effect of estrogen treatment in experimental arthritis. METHODS: Mice with total (total ERalpha-/-) or cartilage-specific (Col2alpha1-ERalpha-/-) inactivation of ERalpha and wild-type (WT) littermates were ovariectomized, treated with E2 or placebo, and induced with antigen-induced arthritis (AIA). At termination, knees were collected for histology, synovial and splenic cells were investigated by using flow cytometry, and splenic cells were subjected to a T-cell proliferation assay. RESULTS: E2 decreased synovitis and joint destruction in WT mice. Amelioration of arthritis was associated with decreased frequencies of inflammatory cells in synovial tissue and decreased splenic T-cell proliferation. E2 did not affect synovitis or joint destruction in total ERalpha-/- mice. In Col2alpha1-ERalpha-/- mice, E2 protected against joint destruction to a similar extent as in WT mice. In contrast, E2 did not significantly ameliorate synovitis in Col2alpha1-ERalpha-/- mice. CONCLUSIONS: Treatment with E2 ameliorates both synovitis and joint destruction in ovariectomized mice with AIA via ERalpha. This decreased severity in arthritis is associated with decreased synovial inflammatory cell frequencies and reduced splenic T-cell proliferation. ERalpha expression in cartilage is not required for estrogenic amelioration of joint destruction. However, our data indicate that ERalpha expression in cartilage is involved in estrogenic effects on synovitis, suggesting different mechanisms for the amelioration of joint destruction and synovitis by E2