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 25 and fibrocartilage breakdown that affects the lives of millions of patients worldwide. Female sex 26 and menopause are both risk factors for knee osteoarthritis, indicating that estrogen could play a 27 role in this disease. In this study, RNA sequencing was used to determine the effects of estrogen 28 treatment on human meniscal cells. Differences in the number and type of differentially expressed 29 genes were seen based on donor sex, estrogen dose, and dosing kinetics. Significantly more 30 differentially expressed genes were seen from male meniscal cells in response to all dosing 31 conditions compared to female cells. Importantly, more genes were differentially expressed in cells 32 treated with continuous dosing of estrogen, which has been shown to stimulate genomic estrogen 33 signaling, as compared to pulsed dosing. Additionally, functional enrichment analysis revealed 34 that many genes of the extracellular matrix, which is important for joint health and injury repair, 35were differentially expressed. Overall, this initial study lays the groundwork for future avenues to 36 pursue the effect of estrogen delivery on regenerative pathways. This critical analysis will then 37 inform the design and implementation of estrogen replacement therapies to promote meniscal 38 health and reduce the onset of osteoarthritis. 39 40

Mutant mice lacking alternatively spliced p53 isoforms unveilAckr4as a male-specific prognostic factor in Myc-driven B-cell lymphomas

“…Together, these data show that Ackr4 is indeed a p53 target gene, although RNAseq data indicated that it is expressed at much lower levels than classical p53 targets like Cdkn1a or Mdm2 in the splenic cells of Eμ-Myc mice (Table S1). Furthermore, Ackr4 was shown to be regulated by Foxl2 and estrogen signalling in ovarian cells (Georges et al, 2014) and 17-β estradiol was recently found to regulate ACKR4 expression in meniscal cells from both sexes, albeit differentially (Knewtson et al, 2020). Accordingly, we observed, in both WT and p53 ΔAS/ΔAS MEFs, that p53 activation with the Mdm2 antagonist Nutlin led to the transactivation of Ackr4, but that a concomitant treatment with 17-β estradiol markedly decreased, or completely abrogated, Ackr4 transactivation (Figure 3I).…”