Circular RNA circPLXNC1 functions as an inhibitor of senescence by regulating autophagy in osteoarthritis.

Objectives: Dysfunctional autophagy during aging is a universal inducer of a variety of degenerative diseases. Here, we aim to identify important non-coding RNAs that are crucial for the regulation of osteoarthritis (OA) and age-associated diseases. In addition, we also aim to explore the underlying molecular mechanisms and potential therapeutic strategies. Methods: RNA sequencing based screening was used to identify potential inflammation and autophagy associated key non-coding RNAs. After the identification of targeting molecular circPLXNC1, we examined its expression profile during OA development and in other aging organs and tissues. In addition, knock down of circPLXNC1 both in vitro and in vivo was used for the functional assays. The downstream targets, miR-130b-5p and ATG7, were also examined. Furthermore, the function of these molecules on autophagy, cell senescence and the progression of OA were also investigated. Results: We identified circPLXNC1 decreased in OA and other aging organs and tissues. CircPLXNC1 acts as a sponge for miR-130b-5p to regulate the expression of autophagy associated enzyme ATG7, which is the direct target of miR-130b-5p. In agreement with the finding that delivery of ATG7 adeno-associated virus (AAV) alleviates OA, the administration of circPLXNC1 AAV exerts similar function to alleviate OA and attenuate the senescence of multiple organs and tissues. Conclusions: We found a potential therapeutic strategy targeting both circPLXNC1 and ATG7 for OA, while circPLXNC1 acted as an inhibitor of senescence in multiple organs and tissues, including cartilage, brain, muscle and adipose.