# Investigating Sex-Linked miRNAs for Potential Osteoarthritis Therapy Biomarkers

## TL;DR

This study explores sex-linked microRNAs in osteoarthritis, identifying seven miRNAs that differ between men and women and may influence disease progression.

## Contribution

The study identifies seven sex-specific miRNAs and their potential targets in early osteoarthritis, offering new insights into sex-based differences in OA.

## Key findings

- Seven miRNAs were significantly upregulated in men compared to women with knee osteoarthritis.
- The miRNAs are associated with ACLY and PIK3R1, which are linked to OA-related pathways and metabolism.
- Sex-specific miRNA expression may influence OA progression through effects on inflammation and catabolic gene expression.

## Abstract

Sex-specific factors can influence the onset and progression of osteoarthritis (OA), yet the molecular mechanisms underlying their impact remain poorly defined. This study investigated whether plasma microRNAs (miRNAs) correlate to sex-dependent OA progression, based on evidence of enhanced spontaneous osteoclastogenesis in peripheral blood mononuclear cells (PBMCs) derived from OA patients. miRNAs were evaluated on OA-plasma (n = 20 men, 20 women with knee OA; KL grade I–II) and their role on OA signaling was investigated through bioinformatic analysis. Seven miRNAs were identified as significantly upregulated in men’ vs. women’ samples: hsa-miR-107, hsa-miR-23a-3p, hsa-miR-103a-3p, hsa-let-7g-5p, hsa-miR-22-3p, hsa-miR-106a-5p, hsa-miR-142-3p, and were associated with OA-related tissues and pathways. Notably, two common targets were identified: Adenosine Triphosphate Citrate Lyase (ACLY), a key enzyme linking citrate metabolism to epigenetic regulation, and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), a component of the phosphatidylinositol-3-kinase PI3K/AKT/mTOR pathway. In men, increased miRNA expression may repress ACLY and PIK3R1, affecting catabolic gene expression, inflammation, and OA progression. Conversely, their lower expression in women may mitigate these effects by counterbalancing the OA-promoting influences driven by sex hormones. A functional validation is needed to confirm miRNA–ACLY/PIK3R1 interactions and their sex-specific roles in early OA pathophysiology.