Abstract
An imbalance in gene expressional events skewing chondrocyte anabolic and catabolic pathways toward the latter causes an aberrant turnover and loss of extracellular matrix proteins in osteoarthritic (OA) articular cartilage. Thus, catabolism results in the elevated loss of extracellular matrix proteins. There is also evidence of an increase in the frequency of chondrocyte apoptosis that compromises the capacity of articular cartilage to undergo repair. Although much of the fundamental OA studies over the past 20 years identified and characterized many genes relevant to pro-inflammatory cytokines, apoptosis, and matrix metalloproteinases (MMPs)/a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS), more recent studies focused on epigenetic mechanisms and the associated role of microRNAs (miRs) in regulating gene expression in OA cartilage. Thus, several miRs were identified as regulators of chondrocyte signaling pathways, apoptosis, and proteinase gene expression. For example, the reduced expression of miR-146a was found to be coupled to reduced type II collagen (COL2) in OA cartilage, whereas MMP-13 levels were increased, suggesting an association between MMP-13 gene expression and COL2A1 gene expression. Results of these studies imply that microRNAs could become useful in the search for diagnostic biomarkers, as well as providing novel therapeutic targets for intervention in OA.
Highlights
The main focus of basic studies designed to unravel the pathology of osteoarthritis (OA) in humans recently employed non-surgical animal models with genetically modified mice as replicas of the human disease [1,2]
(TUNEL)/Hoechst 33258 staining revealed an elevated frequency of apoptosis in freshly isolated chondrocytes from OA cartilage [20], as well as altered patterns of pro-apoptosis and anti-apoptosis factors, exemplified by an analysis of the extrinsic apoptosis pathway which was determined by measurements of Bcl-2-associated X protein( Bax), B-cell lymphoma-2 (Bcl-2), TNF-related apoptosis-inducing ligand (TRAIL), death receptor-5 (DR5), and caspase-3 [21]
This evidence demonstrated that many of the miRs were implicated in targeting those genes that are involved in dysregulated signal transduction (e.g., mitogen-activated protein kinase (MAPK), IGFR1, phosphatidylinositol 3-kinase (PI3K), SMAD1, NF-κB), extracellular matrix (ECM) protein turnover (e.g., COL2A1, COL1A1), pro-inflammatory cytokines (e.g., TNFα, IL1ß, IL6), methylation/demethylation, matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) (e.g., MMP13, TIMP1, ADAMTS5), and autophagy (e.g., Atg3, Atg5, Atg14), many of which were shown to be critical in altering the chondrocyte phenotype characteristic of OA cartilage [51,52,53,54,55,56,57,58,59]
Summary
The main focus of basic studies designed to unravel the pathology of osteoarthritis (OA) in humans recently employed non-surgical animal models with genetically modified mice as replicas of the human disease [1,2]. (TUNEL)/Hoechst 33258 staining revealed an elevated frequency of apoptosis in freshly isolated chondrocytes from OA cartilage [20], as well as altered patterns of pro-apoptosis and anti-apoptosis factors, exemplified by an analysis of the extrinsic apoptosis pathway which was determined by measurements of Bcl-2-associated X protein( Bax), B-cell lymphoma-2 (Bcl-2), TNF-related apoptosis-inducing ligand (TRAIL), death receptor-5 (DR5), and caspase-3 [21] In addition to those genes which effectively reduce chondrocyte viability, other specific genes and signaling pathways, include genes that encode bone morphogenetic proteins, the WNT/β-catenin proteins, leukemia inhibitory factor, hypoxia-inducible factor-1-α/2α (HIF-1α/2α) [22,23], as well as GREM1, FRZB, DKK1, VEGF, EGF [23,24,25], GDF5 [26] genes, and the NOTCH/NF-κB pathway [27]. Pro-inflammatory cytokine-mediated activation of mitogen-activated protein kinase (MAPK) and Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways demonstrated how these signaling pathways control gene expression associated with pro-apoptosis protein synthesis and MMP synthesis, both of which were found to be dysregulated in OA articular chondrocytes [28,29,30,31,32,33]
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