Transcriptome Sequencing Reveals Sex Differences in Human Meniscal Cell Response to Estrogen Based on Dosing Kinetics

Abstract

Osteoarthritis is a disease marked by progressive and irreversible hyaline cartilage and fibrocartilage breakdown that affects the lives of millions of patients worldwide. Female sex and menopause are both risk factors for knee osteoarthritis, indicating that estrogen could play a role in this disease. In this study, RNA sequencing was used to determine the effects of estrogen treatment on human meniscal cells. Differences in the number and type of differentially expressed genes were seen based on donor sex, estrogen dose, and dosing kinetics. Significantly more differentially expressed genes were seen from male meniscal cells in response to all dosing conditions compared to female cells. Importantly, more genes were differentially expressed in cells treated with continuous dosing of estrogen, which has been shown to stimulate genomic estrogen signaling, as compared to pulsed dosing. Additionally, functional enrichment analysis revealed that many genes of the extracellular matrix, which is important for joint health and injury repair, were differentially expressed. Overall, this initial study lays the groundwork for future avenues to pursue the effect of estrogen delivery on regenerative pathways. This critical analysis will then inform the design and implementation of estrogen replacement therapies to promote meniscal health and reduce the onset of osteoarthritis.