Long Intergenic Noncoding RNAs Mediate the Human Chondrocyte Inflammatory Response and Are Differentially Expressed in Osteoarthritis Cartilage.

摘要: Osteoarthritis (OA), typified by degenerative loss of cartilage integrity and joint space narrowing, is a leading cause pain, disability, shortening adult working life throughout the world 1, 2, 3. Unfortunately, at present there no approved treatment that can modify disease progression, resulting in limited therapeutic options for patients 4. In attempting to identify novel therapeutics, inflammation increasingly being recognized as an important driver OA pathology. Histologic analysis, ultrasound, magnetic resonance imaging have all demonstrated evidence synovitis joints 5, 6, 7, with increased cellular infiltration activated B cells T lymphocytes. Indeed, reported not only established OA, but also onset minimal radiographic signs 8. Several proinflammatory cytokines are elevated synovial fluid compared normal healthy 9, cytokine stimulation ex vivo tissue mimics pathologic changes observed within 10. However, key regulators inflammatory response well defined. There now overwhelming microRNA (miRNA) family short noncoding RNAs regulate 11, 12. our group previously identified differentially expressed miRNAs human mediated production matrix metalloproteinase 13 (MMP‐13) tumor necrosis factor (TNF) 13, suggesting role regulating pathology 13. Importantly, RNA sequencing (RNAseq) has multiple families long (lncRNAs), which include antisense RNAs, pseudogenes, intergenic (lincRNAs) 14, 15. Of interest, earlier reports suggest these lncRNAs may be central biologic processes 16, 17, 18, 19, including 20. In support those findings, we recently were upon lipopolysaccharide (LPS)–induced activation innate regulated interleukin‐1β (IL‐1β) IL‐8 21. Currently, little known about expression functional tissue. Their potential importance indicated recent report Fu et al 22, who ∼4,700 from knee (compared controls) using microarray‐based approach. Although preliminary study did examine function lncRNAs, another lincRNA located upstream gene PTGS2 (cyclooxygenase 2 [COX‐2]). This was shown phorbol myristate acetate– LPS‐stimulated monocytes positively COX‐2 23 binding to, relieving action of, repressive p50 component NF‐κB complex 23. As result this action, renamed p50‐associated COX‐2–extragenic (PACER). regulator arachidonic acid pathway subsequent prostaglandin E2 24, putative mediator pain 25, 26. Given observations, pathology, hypothesized PACER, tissue. The aim therefore perform RNAseq order associated primary chondrocytes isolated articular hip OA. We then proceeded assess their involvement examining several “inflammation‐associated” (including PACER) without or profiling determining effect modulating inflammation‐associated lncRNA on chondrocyte response.