Fight Aging!

MicroRNAs are involved in the regulation of gene expression, increasing or decreasing the production of proteins for specific genes, and thereby changing cell behavior. Researchers here find a microRNA that acts to reduce cartilage degeneration in osteoarthritis. Levels are reduced in human osteoarthritic cartilage, and delivering this microRNA as a therapy reduces the level of pathology in a mouse model of injury-induced osteoarthritis. The delivery of manufactured microRNA, intended to alter cell behavior in advantageous ways, is a growing area of development. There is enough industry support to encourage more basic research into this approach to manipulating cell activity. It is a step up from small molecule approaches in terms of off-target effects and size of therapeutic effect, but remains considerably more expensive.

Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes.

We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes.

This data strongly implicates miR-455-5p and -3p in supporting articular cartilage homeostasis by targeting Hif-2α.

Link: https://doi.org/10.1038/s41467-021-24460-7