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The roles of long noncoding RNAs (lncRNAs) in musculoskeletal development, disease, and regeneration remain poorly understood. Here, we identified the novel lncRNA  GRASLND  (originally named  RNF144A-AS1 ) as a regulator of mesenchymal stem cell (MSC) chondrogenesis.  GRASLND , a primate-specific lncRNA, is upregulated during MSC chondrogenesis and appears to act directly downstream of SOX9, but not TGF-β3. We showed that the silencing of  GRASLND  resulted in lower accumulation of cartilage-like extracellular matrix in a pellet assay, while  GRASLND  overexpression – either via transgene ectopic expression or by endogenous activation via CRISPR-dCas9-VP64 – significantly enhanced cartilage matrix production.  GRASLND  acts to inhibit IFN-γ by binding to EIF2AK2, and we further demonstrated that  GRASLND  exhibits a protective effect in engineered cartilage against interferon type II. Our results indicate an important role of  GRASLND  in regulating stem cell chondrogenesis, as well as its therapeutic potential in the treatment of cartilage-related diseases, such as osteoarthritis.

Long non-coding RNA GRASLND enhances chondrogenesis via suppression of the interferon type II signaling pathway