The microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression

• Published in: Nature communications Vol. 10; no. 1; pp. 2876 - 13
• Main Authors: Huang, Jian, Zhao, Lan, Fan, Yunshan, Liao, Lifan, Ma, Peter X., Xiao, Guozhi, Chen, Di
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.06.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/109; 13/31; 13/51; 13/95; 14/32; 14/63; 38; 38/23; 38/77; 38/89; 42/41; 45/90; 59; 631/337/384/331; 64; 64/110; 64/60; 692/699/1670/407; Ablation; AKT protein; Animals; Arthritis; Biocompatibility; Cartilage; Cartilage (articular); Cartilage diseases; Cbfa-1 protein; Cells (biology); Chondrocytes; Chondrocytes - metabolism; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Deceleration; Degeneration; Disease control; Etiology; Homeostasis; Homology; Humanities and Social Sciences; Hyperplasia; Joint diseases; Mesenchymal Stem Cells - physiology; Mesenchyme; Mice; Mice, Knockout; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; multidisciplinary; Nerve growth factor; Osteoarthritis; Osteoarthritis - etiology; Osteoarthritis - metabolism; Osteoarthritis - pathology; Pathogenesis; Peptide Hydrolases - genetics; Peptide Hydrolases - metabolism; Progenitor cells; Science; Science (multidisciplinary); Sclerosis; Stem cells; Synoviocytes; Synoviocytes - metabolism; Viruses
• DOI: 10.1038/s41467-019-10753-5
• ISSN: 2041-1723

Osteoarthritis (OA) is a common, painful disease. Currently OA is incurable, and its etiology largely unknown, partly due to limited understanding of OA as a whole-joint disease. Here we report that two homologous microRNAs, miR-204 and miR-211 , maintain joint homeostasis to suppress OA pathogenesis. Specific knockout of miR-204/-211 in mesenchymal progenitor cells (MPCs) results in Runx2 accumulation in multi-type joint cells, causing whole-joint degeneration. Specifically, miR-204/-211 loss-of-function induces matrix-degrading proteases in articular chondrocytes and synoviocytes, stimulating articular cartilage destruction. Moreover, miR-204 / -211 ablation enhances NGF expression in a Runx2-dependent manner, and thus hyper-activates Akt signaling and MPC proliferation, underlying multiplex non-cartilaginous OA conditions including synovial hyperplasia, osteophyte outgrowth and subchondral sclerosis. Importantly, miR-204 /- 211 -deficiency-induced OA is largely rescued by Runx2 insufficiency, confirming the miR-204 /- 211- Runx2 axis. Further, intraarticular administration of miR-204 -expressing adeno-associated virus significantly decelerates OA progression. Collectively, miR-204 / -211 are essential in maintaining healthy homeostasis of mesenchymal joint cells to counteract OA pathogenesis. Osteoarthritis involves whole-joint tissue degeneration. Here, the authors show that miR-204 and miR-211 in mesenchymal joint cells regulate their proliferation, catabolic and osteogenic responses, and that disease progression is ameliorated by intra-articular miR-204 delivery in mice.