Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis

Abstract

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. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis.

Cartilage Homeostasis and Osteoarthritis

“…To investigate other miRNAs regulated by Sox9 in chondrocytes, a comprehensive microarray analysis was performed. Among several candidates, miRNA-455 showed enhanced expression from both 5p and 3p strands in a Sox9 concentration-dependent manner [ 94 ] and was expressed in chondrocytes in approximately equal amounts from both strands [ 94 ]. To investigate whether this was directly regulated by Sox9, we used ChIp analysis and found a binding site for Sox9 within intron 3 of Col27a1 [ 94 ].…”

Effect of Dietary Polyphenols on Osteoarthritis—Molecular Mechanisms

“…Marked changes in the miRNome are observed in OA’s pathogenesis, reviewed comprehensively by Endisha [ 30 ]. More recently, additional miRNAs involved in knee OA have been identified; these include miR-101, miR-181a, miR-29, miR-9, miR-221, miR-411, miR-455, and miR-132 [ 7 , 31 , 32 , 33 ]. MiRNAs also regulate Wnt/βcatenin pathways [ 34 ], Hypoxia-inducible factor- 1 α (HIF-1) [ 7 ], Hypoxia-inducible factor- 2 α (HIF-2 α), and PTEN/PI3K/AKT signaling pathways [ 30 , 31 ], all of which are implicated in the pathogenesis of OA.…”

Upregulated of ANXA3, SORL1, and Neutrophils May Be Key Factors in the Progressionof Ankylosing Spondylitis

“…In rheumatoid arthritis, the highly dysregulated structure of the microvascular system results in inadequate synovial oxygenation, which continues to increase with the metabolic turnover of the expanding synovial vascular cataract, resulting in a hypoxic microenvironment ( 14 ). Osteoarthritis (OA), a common aging-related disease, is caused by an imbalance between extracellular matrix degradation and and formation, and an abnormal chondrocyte metabolism in response to changes in the inflammatory microenvironment may play a key role in cartilage degeneration and OA progression; under environmental stress conditions, chondrocytes may adapt to changes in the microenvironment by altering metabolic pathways, which may be oxidative phosphorylation to glycolysis ( 15 , 16 ). However, the specific mechanisms by which hypoxia plays a role in the development of ankylosing spondylitis, a chronic inflammatory disease, remain unclear, and there is little research on hypoxia in AS.…”