Oxidative Stress, MicroRNAs, and Long Non-Coding RNAs in Osteoarthritis Pathogenesis: Cross-Talk and Molecular Mechanisms Involved

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease, characterized by articular cartilage degradation, synovial inflammation, and ligament lesions. Non-coding RNAs (ncRNAs) do not encode any protein products and play a fundamental role in regulating gene expression in several physiological processes, such as in the regulation of cartilage homeostasis. When deregulated, they affect the expression of genes involved in cartilage degradation and synovial inflammation, contributing to the onset and progression of OA. Oxidative stress is also involved in the pathogenesis of OA by contributing to the inflammatory response, degradation of the extracellular matrix, and induction of chondrocyte apoptosis. Studies in the literature show a reciprocal relationship between the altered expression of a number of ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), and oxidative stress. The aim of this review is to highlight the role of oxidative stress, miRNAs, and lncRNAs and their cross-talk in OA in order to understand the main molecular mechanisms involved and to identify possible targets that may be useful for the identification and development of new diagnostic and therapeutic approaches for this disease.

Keywords: cartilage degradation; lncRNAs; miRNAs; osteoarthritis; oxidative stress.

Figure 1

Intricate connections among MMPs, cytokines, miRNAs, lncRNAs, and oxidative stress. Abbreviations: ROS, reactive oxygen species; NF-κB, nuclear factor kappa B; MAPKs, mitogen-activated protein kinases; TNFα, tumor necrosis factor α; MMP, metalloproteinase; IL-1β, interleukin-1β; IL-6, interleukin-6; PTEN, phosphatase and tensin homologue of chromosome 10 PI3K/Akt, phosphatidylinositol-3-kinase/protein kinase B; Nrf2/HO-1, nuclear factor erythroid 2-related factor 2/heme oxygenase-1; JAK/STAT, Janus kinase/signal transducer and activator of transcription. Image created by BioRender (https://app.biorender.com, accessed on 30 June 2025).

Figure 2

Principal molecular mechanisms involved in the MAPK, NF-κB, and PI3K/Akt signaling pathways activated by oxidative stress in OA. Abbreviations: PI3K/Akt, phosphatidylinositol-3-kinase/protein kinase B; MAPKs, mitogen-activated protein kinases; NF-κB, nuclear factor kappa B; ERK1/2, extracellular signal regulated kinases 1 and 2; JNK, c-Jun N-terminal kinase; MEK1/2, MAPK kinases; ADAMTS5, disintegrin and metalloproteinase with thrombospondin motifs 5; MMP, metalloproteinase; HIF2α, hypoxia-inducible factor 2 alpha; iNOS, inducible nitric oxide synthase; KLF-10, Krüppel-like factor 10; COX, cyclooxygenase; ECM, extracellular matrix. (−) Downregulated. (+) Upregulated. Image created by BioRender (https://app.biorender.com, accessed on 30 June 2025).

Figure 3

Principal microRNAs and targets involved in inflammation and cartilage destruction in OA. Abbreviations: NF-κB, nuclear factor kappa B; PI3K/Akt, phosphatidylinositol-3-kinase/protein kinase B; P2X7R, purinergic P2X7 receptor; VCAM-1, vascular cell adhesion molecule-1; IkBα, inhibitor kappa B-alpha; BCL2L12, B cell leukemia 2-like 12; MAPKs, mitogen-activated protein kinases; ECM, extracellular matrix; MMP, metalloproteinase; ADAMTS5, disintegrin and metalloproteinase with thrombospondin motifs 5; SP1, specificity protein 1; WISP1, Wnt-1 inducible signaling pathway protein 1; PTHrP, parathyroid hormone-related protein; MKK4, mitogen-activated protein kinase kinase 4; HBEGF, heparin-binding EGF-like growth factor; Sirt1, sirtuin-1. (−) Downregulated. (+) Upregulated. Image created by BioRender (https://app.biorender.com, accessed on 30 June 2025).

Figure 4

Principal signaling and effects of miRNAs related to oxidative stress. Abbreviations: ROS, reactive oxygen species; ECM, extracellular matrix; KPNA3, karyopherin subunit alpha 3; NF-κB, nuclear factor kappa B; MMP, metalloproteinase; MyD88, myeloid differentiation primary response 88; Nrf2/HO-1, nuclear factor erythroid 2-related factor 2/heme oxygenase-1; TLR4, Toll-like receptor 4; IKKα, inhibitory kappa B kinase α; Sirt1, sirtuin-1; COX2, cyclossigenase-2. (−) Downregulated. (+) Upregulated. Image created by BioRender (https://app.biorender.com, accessed on 30 June 2025).

Figure 5

Effects of MALAT1 upregulation in OA. Abbreviations: NF-κB, nuclear factor kappa B; ADAMTS5, disintegrin and metalloproteinase with thrombospondin motifs 5; PI3K/Akt/mTOR, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin; MyD88, myeloid differentiation primary response 88. (−) Downregulated. (+) Upregulated. Image created by BioRender (https://app.biorender.com, accessed on 30 June 2025).

Figure 6

Effects of deregulating HOTAIR and PACER in OA. Abbreviations: COX2, cyclossigenase-2; FUT2, α-1,2-fucosyltransferase; PI3K/Akt, phosphatidylinositol-3-kinase/protein kinase B; p38 MAPK, p38 mitogen-activated protein kinase; PTEN, phosphatase and tensin homolog of chromosome 10. (−) Downregulated. (+) Upregulated. Image created by BioRender (https://app.biorender.com, accessed on 30 June 2025).