Estrogen mediated differential protein regulation and signal transduction in rheumatoid arthritis

Abstract

Exploration of the dual and opposing facets of estrogen (E2) necessitate a clear understanding to diminish the controversy of estrogen regulation in averting the systemic, autoimmune, joint degrading disorder, rheumatoid arthritis (RA). Experimental evidences consider estrogen as a pivotal enzyme to modulate the disease progression via managing several cellular mechanisms targeting inflammatory markers such as TNF, ILs, NF-κB and other regulatory proteins like MMPs impeding joint erosion and cartilage degradation. E2 modulates cellular signalling associated with inflammation, oxidative stress, related cardiovascular risk and miRNA regulation during RA progression. Studies determining E2 regulation in RA complicate the resemblance of the outcome as they represent both hyper and hypo level of E2 linked to the disease. Although some reports deliver E2 as malign, there is now increasing evidence of rendering protection dose dependently. Variation in estrogen level cause differential expression of certain proteins and their related signalling which directly or indirectly linked to RA pathogenesis. This review summarizes the variations in protein expression levels by focusing on the in vitro, in vivo and clinical studies of E2 deficiency and treatment. Construction of PPI network, GO and KEGG pathway enrichment analysis of the differentially expressed proteins assist in hypothesizing a potential molecular mechanism of E2 in RA via in silico studies. Targeting these differential proteins can emerge a new path for developing advanced therapeutic strategies.

Estrogen receptors, ERK1/2 phosphorylation and reactive oxidizing species in red blood cells from patients with rheumatoid arthritis

“…Estrogens are believed to modulate several key features of the immune system, by regulating intracellular signaling linked to inflammation and oxidative stress, antigen specific responses, as well as cytokine production ( Alpizar-Rodrıguez et al, 2017 ; Chakraborty et al, 2022 ). The estrogens effects depend on both their concentration and distribution of ER-expressing immune cells ( Chakraborty et al, 2022 ).…”

“…Estrogens are believed to modulate several key features of the immune system, by regulating intracellular signaling linked to inflammation and oxidative stress, antigen specific responses, as well as cytokine production ( Alpizar-Rodrıguez et al, 2017 ; Chakraborty et al, 2022 ). The estrogens effects depend on both their concentration and distribution of ER-expressing immune cells ( Chakraborty et al, 2022 ). The same expression of ERs can be modulated by estrogen, as the case of ER-α, but not ER-β, and increased after the treatment of human fibroblast-like synovial cells with 17β-estradiol ( Mitani et al, 2005 ).…”

Revisiting Resveratrol as an Osteoprotective Agent: Molecular Evidence from In Vivo and In Vitro Studies

“…OPG inhibited RANK activation by RANKL, reducing osteoclastogenesis [112,113]. OPG expression and production were regulated by cytokines such as IL-6 and TNFα [114], steroid hormones (17β estradiol) [115], transforming growth factor (TGFβ) [116], and bone morphogenetic proteins (BMPs) [117]. Glucocorticoids, prostaglandin E2, fibroblastic growth factor, and parathyroid hormone (PTH) were all known to suppress the expression of OPG [118].…”

Unveiling the Nexus: Cellular Metabolomics Unravels the Impact of Estrogen on Nicotinamide Metabolism in Mitigating Rheumatoid Arthritis Pathogenesis

“…Furthermore, estrogen also regulates the innate immune response by increasing IgG-Fc sialylation in post-menopausal women with RA [18]. We recently reviewed the effect of estrogen on the differential proteome of RA, along with in silico analysis that showed various signaling pathways and related proteins involved in the inflammatory progression of RA were the targets of estrogenic therapeutic efficacy [19].…”