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

Immunomodulation by estrogen and estren

Estrogen affects the development and regulation of the immune system. Treatment of gonadectomized mice with estrogen results in suppression of T and B lymphopoiesis, as well as decreased delayed type hypersensitivity reaction, granulocyte mediated inflammation and levels of IL-6 in serum. Conversely, immunoglobulin production is stimulated by estrogen. The effects of estrogen are mediated through the estrogen receptors (ER), ERa and ERb, which are ligand activated transcription factors that induce expression of specific estrogen responsive genes. The aims of this thesis were to investigate the role of ERs on B lymphopoiesis and immunoglobulin production, as well as on the aged immune system. Furthermore, the ER specific effects of the synthetic molecule estren on T and B lymphopoiesis, T cell-mediated inflammation and submandibular glands were studied. ER knock-out mice lacking ERa, ERb or both ERa and ERb, were gonadectomized and treated with 17b-estradiol-3-benzoate (E2) or 4-estren-3a,17b-diol (estren). We found that both ERa and ERb are required for the estrogen-induced decreased frequency of B lymphopoietic cells in the bone marrow. ERa alone is necessary for the estrogen-mediated, as well as for the age-induced, increased frequency of immunoglobulin producing B cells. We could also show that estren inhibits inflammation through ER-mediated pathways, while the inhibitory effects on T and B lymphopoiesis are not dependent on ERs. Furthermore, estren promotes an androgen phenotype in submandibular glands that is independent of ERs. In conclusion, our results show that the effects of estrogen on the immune system are mainly mediated via ERa, but signalling through ERb is necessary for complete inhibitory effect on B lymphopoiesis. Furthermore, estren treatment induces effects on lymphopoiesis and submandibular glands that are not mediated through ERs, but instead possibly through the androgen receptor

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