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Evidence that miR-146a attenuates aging- and trauma-induced osteoarthritis by inhibiting Notch1, IL-6, and IL-1 mediated catabolism

Evidence that miR-146a attenuates aging- and trauma-induced osteoarthritis by inhibiting Notch1, IL-6, and IL-1 mediated catabolism

Aging Cell 17(3): E12752

Primary osteoarthritis (OA) is associated with aging, while post-traumatic OA (PTOA) is associated with mechanical injury and inflammation. It is not clear whether the two types of osteoarthritis share common mechanisms. We found that miR-146a, a microRNA-associated with inflammation, is activated by cyclic load in the physiological range but suppressed by mechanical overload in human articular chondrocytes. Furthermore, miR-146a expression is decreased in the OA lesions of human articular cartilage. To understand the role of miR-146a in osteoarthritis, we systemically characterized mice in which miR-146a is either deficient in whole body or overexpressed in chondrogenic cells specifically. miR-146a-deficient mice develop early onset of OA characterized by cartilage degeneration, synovitis, and osteophytes. Conversely, miR-146a chondrogenic overexpressing mice are resistant to aging-associated OA. Loss of miR-146a exacerbates articular cartilage degeneration during PTOA, while chondrogenic overexpression of miR-146a inhibits PTOA. Thus, miR-146a inhibits both OA and PTOA in mice, suggesting a common protective mechanism initiated by miR-146a. miR-146a suppresses IL-1β of catabolic factors, and we provide evidence that miR-146a directly inhibits Notch1 expression. Therefore, such inhibition of Notch1 may explain suppression of inflammatory mediators by miR-146a. Chondrogenic overexpression of miR-146a or intra-articular administration of a Notch1 inhibitor alleviates IL-1β-induced catabolism and rescues joint degeneration in miR-146a-deficient mice, suggesting that miR-146a is sufficient to protect OA pathogenesis by inhibiting Notch signaling in the joint. Thus, miR-146a may be used to counter both aging-associated OA and mechanical injury-/inflammation-induced PTOA.

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Accession: 063602030

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PMID: 29575548

DOI: 10.1111/acel.12752

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