Estrogen mediated differential protein regulation and signal transduction in rheumatoid arthritis

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.