Journal
GENES & DEVELOPMENT
Volume 24, Issue 11, Pages 1173-1185Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1915510
Keywords
MicroRNA; miR-140; osteoarthritis; cartilage; Adamts-5
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Funding
- NIH [AR050631, AR056120, AG007996, AG033409]
- Arthritis National Research Foundation
- Arthritis Foundation
- Ministry of Health, Labour, and Welfare
- Genome Network Project (MEXT)
- grants-in-aid for Scientific Research (MEXT)
- National Institute of Biomedical Innovation, Research on Child Health and Development
- Japan Health Sciences Foundation
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Osteoarthritis (OA), the most prevalent aging-related joint disease, is characterized by insufficient extracellular matrix synthesis and articular cartilage degradation, mediated by several proteinases, including Adamts-5. miR-140 is one of a very limited number of noncoding microRNAs (miRNAs) specifically expressed in cartilage; however, its role in development and/or tissue maintenance is largely uncharacterized. To examine miR-140 function in tissue development and homeostasis, we generated a mouse line through a targeted deletion of miR-140. miR-140(-/-) mice manifested a mild skeletal phenotype with a short stature, although the structure of the articular joint cartilage appeared grossly normal in 1-mo-old miR-140(-/-) mice. Interestingly, miR-140(-/-) mice showed age-related OA-like changes characterized by proteoglycan loss and fibrillation of articular cartilage. Conversely, transgenic (TG) mice overexpressing miR-140 in cartilage were resistant to antigen-induced arthritis. OA-like changes in miR-140-deficient mice can be attributed, in part, to elevated Adamts-5 expression, regulated directly by miR-140. We show that miR-140 regulates cartilage development and homeostasis, and its loss contributes to the development of age-related OA-like changes.
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