Sex-Specific Modulation of Gene Expression by 17beta-Estradiol in Human Meniscal Cells: Pathways to Targeted Osteoarthritis Therapies

Abstract

Osteoarthritis (OA) disproportionately affects women, and estrogen has been implicated in cartilage and joint homeostasis, yet its effects on meniscal fibrochondrocytes (MFCs), and whether those effects differ by sex, remain poorly defined. We reanalyzed a publicly available RNA-sequencing dataset (Gene Expression Omnibus, GSE199087) comprising human MFCs from a male and a female donor treated with 17{beta}-estradiol (E2) or vehicle. Differential expression, Gene Set Enrichment Analysis, Enrichr, and iLINCS were integrated to identify the transcriptional programs modulated by E2 in each sex. In female MFCs, E2 upregulated pathways governing DNA replication, cell-cycle progression, and genomic maintenance (e.g., MCM8, BRCA1, RAD51), while downregulating inflammatory and extracellular matrix-degrading genes, including MMP1, IL12A, CXCL12, and MYD88. In male MFCs, E2 instead upregulated chromatin remodeling and developmental signaling programs, led by SRCAP, ERCC6, and NOTCH1, and downregulated antigen presentation and mitochondrial genes. These divergent responses indicate that E2 engages distinct, sex-specific transcriptional programs in MFCs, with the female profile favoring proliferation and matrix preservation. Although derived from a limited sample and therefore hypothesis-generating, these findings nominate candidate mechanisms underlying sex differences in meniscal biology and OA susceptibility, and warrant validation in larger, sex-balanced cohorts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/740612v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@16026fforg.highwire.dtl.DTLVardef@1a048acorg.highwire.dtl.DTLVardef@3246corg.highwire.dtl.DTLVardef@4c598b_HPS_FORMAT_FIGEXP M_FIG C_FIG