Researchers identified a circulating microRNA, miR-126-3p, as a candidate biomarker for the detection and monitoring of radiographic knee osteoarthritis at moderate stages.
Circulating miR-126-3p levels were found to be consistently elevated in individuals with radiographic knee osteoarthritis (OA) (Kellgren-Lawrence grade ≥2) across four independent cohorts from the United States, France, Norway, and Mexico.
MicroRNAs are small, noncoding RNA molecules that regulate gene expression and can be quantified through minimally invasive blood tests. Because OA lacks a validated blood-based biomarker, researchers are investigating microRNAs for their diagnostic and mechanistic potential.
In the current study, investigators reanalyzed two previously published microRNA sequencing datasets using a customized pipeline and validated their findings in additional human samples and a surgical mouse model of OA. In the Henry Ford Health cohort (n = 145), plasma miR-126-3p levels were significantly elevated in patients with knee OA but not in those with hip OA. Models incorporating miR-126-3p alongside age, sex, and body mass index improved diagnostic accuracy, achieving 91% sensitivity and 71% specificity.
Tissue analysis revealed that miR-126-3p was most highly expressed in the infrapatellar fat pad, synovium, and subchondral bone. The fat pad exhibited the highest levels of primary and mature miR-126-3p expression, indicating it may be a source of circulating miR-126-3p, whereas subchondral bone, which had high accumulation but low production, may serve as a sink.
To assess functional relevance, researchers administered miR-126-3p mimics to mice with surgically induced knee OA via intravenous or intra-articular injection. Treated mice showed reduced cartilage degradation and synovitis. In vitro, transfection of OA tissue explants with miR-126-3p mimic suppressed angiogenesis-related gene expression, including VEGFA, IRS1, ADAM9, and SPRED1.
Further reductions were observed in genes involved in osteogenesis (RUNX2, OSX, OCN), adipogenesis (LEP, ADIPOQ), and inflammation (IL1B, IL6, TNFA)—processes that are considered secondary to angiogenesis in OA pathophysiology.
The authors concluded that miR-126-3p is consistently elevated in radiographic knee OA and may function as both a minimally invasive biomarker and a mechanistic modulator of disease progression through its antiangiogenic effects. They noted that further studies are needed to evaluate clinical applicability.
The authors declared no competing interests.
Source: Nature Communications
