An inducible long noncoding RNA, LncZFHX2, facilitates DNA repair to Imediate osteoarthritis pathology

Cartilage homeostasis is essential for chondrocytes to maintain proper phenotype and metabolism. Because adult articular cartilage is avascular, chondrocytes must survive in low oxygen conditions, and changing oxygen tension can significantly affect metabolism and proteoglycan synthesis in these cells. However, whether long noncoding RNA participate in cartilage homeostasis under hypoxia has not been reported yet. Here, we first identified Lnc2PHX2 as a lncRNA upregulated under physiological hypoxia in cartilage, specifically by HIP-1 LacZFHX2 knockdown simultaneously accelerated cellular senescence, targeted multiple components of extra- cellular matrix metabolism, and increased DNA damage in chondrocytes. Through a series of in vitro and in vivo experiments, we identified that LncZFHX2 performed a novel function that regulated RIP1 expression through forming a transcription complex with KLF4 and promoting chondrocyte DNA repair. Moreover, chondrocyte- conditional knockout of LacZPHX2 accelerated injury-induced cartilage degeneration in vivo. In conclusion, we identified a hypoxia-activated DNA repair pathway that maintaina matrix homeostasis in osteoarthritis cartilage.

Automated summary

This study identified a hypoxia-activated long noncoding RNA involved in cartilage homeostasis and demonstrated its function in maintaining matrix homeostasis through regulating DNA repair pathway in chondrocytes.