+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 063602030

Download citation: RISBibTeXText

PMID: 29575548

DOI: 10.1111/acel.12752


Related references

MicroRNA-146a protects against LPS-induced organ damage by inhibiting Notch1 in macrophage. International Immunopharmacology 63: 220-226, 2018

MiR-146a regulates IL-6 production in lipopolysaccharide-induced RAW264.7 macrophage cells by inhibiting Notch1. Inflammation 37(1): 71-82, 2014

MiR-146a attenuates liver fibrosis by inhibiting transforming growth factor-β1 mediated epithelial-mesenchymal transition in hepatocytes. Cellular Signalling 58: 1-8, 2019

Hyperoside attenuates renal aging and injury induced by D-galactose via inhibiting AMPK-ULK1 signaling-mediated autophagy. Aging 10(12): 4197-4212, 2018

MiR-146a modulates macrophage polarization by inhibiting Notch1 pathway in RAW264.7 macrophages. International Immunopharmacology 32: 46-54, 2016

Denbinobin upregulates miR-146a expression and attenuates IL-1β-induced upregulation of ICAM-1 and VCAM-1 expressions in osteoarthritis fibroblast-like synoviocytes. Journal of Molecular Medicine 92(11): 1147-1158, 2014

Gastrodin reduces IL-1β-induced apoptosis, inflammation, and matrix catabolism in osteoarthritis chondrocytes and attenuates rat cartilage degeneration in vivo. Biomedicine and PharmacoTherapy 97: 642-651, 2018

Necrostatin-1 Attenuates Trauma-Induced Mouse Osteoarthritis and IL-1β Induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes. Frontiers in Pharmacology 9: 1378, 2018

Propofol attenuates angiotensin II-induced vasoconstriction by inhibiting Ca2+-dependent and PKC-mediated Ca 2+ sensitization mechanisms. Journal of Anesthesia 26(5): 682-688, 2012

Evidence for presenilin-mediated Notch1 cleavage and presenilin-independent Notch1 signaling in mammalian cells. Society for Neuroscience Abstracts 26(1-2): Abstract No -298 11, 2000

Catalpol attenuates lipopolysaccharide-induced inflammatory responses in BV2 microglia through inhibiting the TLR4-mediated NF-κB pathway. General Physiology and Biophysics 38(2): 111-122, 2019

PARP-1 inhibitor, DPQ, attenuates LPS-induced acute lung injury through inhibiting NF-κB-mediated inflammatory response. Plos one 8(11): E79757, 2013

Epigallocatechin gallate (EGCG) attenuates infrasound-induced neuronal impairment by inhibiting microglia-mediated inflammation. Journal of Nutritional Biochemistry 25(7): 716-725, 2014

Lycopene attenuates aluminum-induced hippocampal lesions by inhibiting oxidative stress-mediated inflammation and apoptosis in the rat. Journal of Inorganic Biochemistry 193: 143-151, 2019

Isoflurane attenuates lipopolysaccharide-induced acute lung injury by inhibiting ROS-mediated NLRP3 inflammasome activation. American Journal of Translational Research 8(5): 2033-2046, 2016