Research has linked osteoarthritis of the knee to an RNA molecule that exacerbates inflammation and triggers cartilage damage. A new study, published in Science, clarifies the molecular origins of this debilitating condition.
Investigators based at the Southern Medical University in China, gathered data from patient cartilage samples and mice. The work could inform ongoing efforts to target the molecular mechanisms that drive osteoarthritis (OA) in patients.
“Inflammatory responses play a critical role in aggravating OA pathogenesis and cause OA pain. Studies on the role of inflammatory mediators and the mechanisms of inflammatory signalling in OA cartilage lesions are of great importance,” the authors report.
Many factors can contribute to osteoarthritis, including joint injury, mechanical stress, cellular senescence, and age-associated increases in systemic inflammation.
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein that regulates immunity and controls cytokine production and cell survival. Scientists have previously observed a major role for inflammatory factors such as the NF-κB protein in inflammatory osteoarthritis of the knee, one of the most common forms of the condition.
Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma.
The new study demonstrates that a long noncoding RNA (lncRNA) molecule called PILA can worsen osteoarthritis by amplifying activation of the NF-κB pathway.
“We believe that our study provides previously unidentified insights into the complex regulation of NF-κB signalling and a potentially new therapeutic target for osteoarthritis,” state the authors.
Long noncoding RNA’s role
First, the scientists detected abnormally high concentrations of PILA in samples of damaged cartilage from patients with osteoarthritis. The lncRNA also became active in human cartilage cells exposed to the pro-inflammatory molecule TNF (tumour necrosis factor). However, knocking out PILA inhibited NF-κB signalling in the cells and prevented cell death.
Further studies demonstrated that PILA amplified osteoarthritis-linked signalling by altering the enzyme DHX9. This subsequently triggered the expression of another enzyme called TAK1 that supports NF-κB signaling.
“More and more evidence show that lncRNAs act as epigenetic modifiers to regulate gene expression,” the authors note.
The team also found that delivering PILA to the knee joints of mice with a viral vector degraded joint cartilage. In addition, it aggravated experimentally-induced osteoarthritis in the animals.
The authors call for further research to define the role of PILA in normal joint biology and to investigate whether the lncRNA could serve as a therapeutic target in patients with osteoarthritis.
Written by Poppy Jayne Morgan, Front Line Genomics
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