Using MicroRNAs-122 and 451 to Prevent the Responses Associated with Osteoarthritis

Objectives: Osteoarthritis (OA) can affect the temporomandibular joint, particularly in response to teeth grinding or clenching. It is characterized by inflammation and increased production of proteolytic enzymes, suggesting that interrupting these pathways could target OA progression. MicroRNAs (miR), which are short segments of RNA that bind to mRNA preventing translation, are modulated during OA progression, suggesting a potential therapeutic role. Here, we evaluated expression of miR-122 and miR-451 in OA and normal articular cartilage and examined their effects on rat articular chondrocytes (rArCs) in-vitro.
Methods: Bilateral ACLT was used to induce post-traumatic OA in Sprague Dawley rats (n=9) with sham animals as controls (n=8). Rats were killed on post-surgery d70. Samples were scanned using micro-CT; histologic sections were stained with Masson’s trichrome, and PCR of tissue RNA was performed. rArCs were transfected with miR-122 or miR-451 for 24hrs. Confluent cells were treated +/- IL-1β for 24hrs. Matrix metalloproteinase-13 (MMP-13), prostaglandin-E2 (PGE2) and a multiplex protein array were analyzed. Inhibitor experiments were used to verify changes due to these miRs.
Results: Micro-CT and histology showed a decrease in cartilage-surface/cartilage-volume and in surface density of the subchondral bone in ACLT compared to sham, confirming OA. miR-122 and miR-451 were elevated in the OA articular cartilage but not in subchondral bone. miR-122 prevented increased MMP-13 and PGE2 induced by IL-1b, whereas miR-451 exacerbated IL-b1’s effect. miR-122 decreased IL-1a, IL-2, Il-4, IL-6, GM-CSF, MIP-1A, RANTES and VEGF induced by IL-1b, while miR-451 increased all but IL-1α, RANTES and VEGF. miR-122 inhibitor increased MMP-13 and PGE2 whereas miR-451 inhibitor had no effect.
Conclusions: miR-122 and miR-451 are increased in OA cartilage. miR-122 expression prevents increases in pro-inflammatory and catabolic molecules induced by IL-1β while miR-451 exacerbates these responses. Using miRs that inhibit OA progression could be a powerful therapeutic.