New research published in Science Translational Medicine implicates microRNA-204 in the mechanism by which oxidative stress results in altered chondrocyte metabolism and cartilage loss in osteoarthritis (OA).

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“The molecular pathways governing the senescent phenotypes of chondrocytes in OA are not well-characterized,” says Jin-Hong Kim, corresponding author of the new study.

The researchers first began studying miR-204 after pulling it from a small RNA sequencing screen of primary mouse chondrocytes that had been cultured in hyperoxic conditions to induce oxidative stress. They subsequently found that miR-204 is highly expressed in cartilage from patients with OA, specifically in parts of the cartilage that are most damaged.

By treating chondrocytes in vitro with the miRNA, the researchers showed that a major effect of miR-204 is to change chondrocyte activity and metabolism. miR-204 made these cells produce less extracellular matrix (ECM) and this ECM had a low proteoglycan content, similar to chondrocytes in OA cartilage.

Furthermore, intra-articular injection of miR-204 resulted in loss of proteoglycans and in cartilage damage and exacerbated cartilage loss in mice after destabilization of the medial meniscus (DMM; as a model of OA).

The researchers think that by reducing proteoglycan biosynthesis, the cartilage becomes less able to cope with load bearing.

Notably, intra-articular injection of an anti-miR oligonucleotide against miR-204 into DMM mice resulted in recovery of chondrocyte proteoglycan synthesis. These mice were able to put more weight on the affected leg than mice injected with control anti-miR oligonucleotides, indicating a reduction in pain.

miR-204 is highly expressed in cartilage from patients with OA

“However, to treat chronic diseases such as OA in this manner would require repeated dosing of anti-miR oligonucleotides as they are not particularly stable,” cautions Kim. “So we are now attempting to develop protective vehicles or RNA modification methods to come up with a new therapeutic strategy to maximize the injection interval. Furthermore, we are designing RNA-based therapeutics using chondrocyte-affinity peptides for targeted intra-articular delivery.”