Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis
Abstract
:1. Introduction
2. Evidence for the Presence of Low-Grade Inflammation in Osteoarthritis
3. Sox-9, NF-kB and Proinflammatory Cytokines Mediate Hypertrophy and Aberrant Signal Transduction Leading to Cartilage Deterioration
4. Hypertrophic Differentiation and Chondrocyte Phenotype
5. Altered Carbohydrate Metabolism Is Linked to Catabolic Reprogramming with Common Features of Pro-Inflammatory Phenotype in Osteoarthritic Chondrocytes
6. Central Metabolic Pathways’ Reprogramming and Mitochondrial Dysfunction Are Hallmarks of Hypertrophy and Senescence
7. Imbalance of Hypoxia-Inducible Factors Regulate Inflammatory Signals and Cartilage Destruction
8. Senescent Chondrocytes Possess Remarkable Pro-Inflammatory and Catabolic Signatures
9. Mechanosensing, the YAP/TAZ Signaling, Oxidative Stress and Chondrocyte Senescence
10. The Energy Sensor mTOR Protein Complex Regulates Chondrocyte Senescence
11. Regulation of Senescence at the Post-Transcriptional Level with miR and Other Small Non-Coding RNAs Modulates the Inflammatory Signature
12. Senolysis Has Beneficial Effects in Experimental Conditions
13. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ACAN | aggrecan |
ACLT | Anterior Cruciate Ligament Transection |
ADAMTS 4,5 | A Disintegrin and Metalloproteinase with Thrombospondin motifs |
Akt | Protein kinase B |
AMPKα | AMP-activated protein kinase alpha |
BMP | Bone morphogenetic protein |
CCL-27 | C-C motif chemokine ligand 27 |
CD | Cluster of differentiation |
cGAS | Cyclic GMP-AMP |
COL10A1 | Collagen type X alpha chain 1 |
COL2A1 | Collagen type II alpha chain 1 |
CXCL8 | CXC motif chemokine ligand 8 |
DMEM | Dulbecco’s Modified Eagle Medium |
FADH2 | Flavin-adenine dinucleotide, reduced |
FRZB | Frizzled-related protein |
G-6-P DH | Glucose 6-phosphate dehydrogenase |
GADD45 | Growth arrest and DNA damage inducible 45 |
GLUT-1 | Glucose transporter 1 |
GROα | Chemokine C-X-C motif ligand 1 |
GSK3 | Glycogen synthase kinase 3 |
HDAC | Histone deacetylase |
HIF1α, 2α | Hypoxia inducible factor 1α, 2α |
HK | Hexokinase |
HMGB2 | High-mobility group protein 2 |
IGFBP7 | Insulin-like growth factor (IGF)-binding protein |
IHH | Indian hedgehog |
IKK | Inhibitory-kB kinase |
IL | Interleukin |
JNK | Jun N-terminal kinase |
LATS 1 | Large tumor suppressor kinase 1 |
Lcn2 | Lipocalin 2 |
LDH | Lactate dehydrogenase |
LPS | Lipopolysaccharide |
MAPK | Mitogen activated protein kinase |
MCP-1 | monocyte chemoattractant protein-1 |
miR | micro RNA |
MMP | Matrix metalloproteinase |
MOB1A/B | Mps one binder kinase activator 1 A/B |
mPGES-1 | Microsomal prostaglandin E synthase 1 |
MST1/2 | Mammalian sterile 20-like kinase 1/2 |
mTORc | Mammalian target of rapamycin complex 1 |
NADH+ | Nicotinamide-adenine dinucleotide, reduced |
NADPH+ | Nicotinamide-adenine dinucleotide phosphate, reduced |
NDRG2 | NMYC downstream-regulated gene 2 |
NFkB | Nuclear factor kappa B |
NLRP3 | NLR family pyrin domain containing 3 |
NO | Nitrogen monoxide |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
OARSI | Osteoarthritis Research Society International |
OXPHOS | Oxidative phosphorylation |
PAI-1 | Plasminogen activator inhibitor-1 |
PGC1α | Peroxisome proliferator-activated receptor-gamma coactivator |
PI3K | Phospho-inositole 3-kinase |
PKM2 | Piruvate kinase M2 |
PPAR | Peroxisome Proliferator-Activated Recpetor |
PTHrP | Parathormone-related peptide |
RAGE | Receptor of end-glycation products |
RANKL | Receptor activator for nuclear factor kappa B ligand |
ROS | Reactive oxygen species |
RunX2 | Runt-related transcription factor 2 |
SASP | Senescence-associated secretory pattern |
SAV | Salvador |
SIRT 1,6 | Sirtuin 1,6 |
SMAD | Suppressor of mothers against Decapentaplegic |
Sox-9 | Sex-determining region Y-type (SRY) high mobility group (HMG) box family of DNA binding protein 9 |
STING | Stimulator of interferon genes |
TAZ | Transcriptional coactivator with PDZ-binding motif |
TCA | Tricarboxylic acid cycle |
TGF-β | Transforming growth factor beta |
TIMP-1 | Tissue inhibitor of metalloproteinases 1 |
TLR-4 | Toll-like Receptor 4 |
TNF-α | Tumor necrosis factor alpha |
TRPV4 | Transient Receptor Potential Vanilloid 4 |
TSPYL2 | Testis-specific Y-encoded-like protein 2 |
VEGF | Vascular endothelial growth factor |
YAP | Yes-associated protein |
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Reference | Study Goals | Change of Mediators | Other Results |
---|---|---|---|
Circulating mediators of inflammation | |||
Sohn D.H. et al. [8] | Proteomic analysis of serum/synovial fluid (SF) | Newly identified NF-kB-related proteins, cytokine receptors (IL-12R, IL-18R, IL-20R) and macrophage-derived inflammatory proteins in synovial fluid High levels of IL-6 in SF | Upregulation of histone deacetylase Upregulated plasma proteins, protease inhibitors, NF-kB subunits and regulators, cytokines (IL-6, MCP-1, VEGF), complement fragments in OA sera |
Gobezie R. et al. [11] | Synovial protein analysis in OA patients and healthy | ↑ Albumin, fibrinogen, α1-microglobulin/bikunin precursor, α2-macroglobulin, haptoglobin, complement C3 ↓ Cystatin C, aggrecan | 18 Proteins differentially expressed between OA and healthy |
Krenytska D. et al. [12] | Comparative analysis of plasma cytokines and growth factors in OA, OA + COVID-19 and controls | ↑ IL-1β in OA ↓ TNF-α, NF-kB in OA ↓ VEGF, PDGF, FGF2 in OA No significant changes in IL-6 and HIF-1α | Maximum values of IL-1β, less pronounced decrease in TNF-α and NF-kB |
Wang Z.W. et al. [14] | Serum protein analysis in OA patients | ↑ IL-1β, IL-6, TNFα, VEGF in OA patients vs. controls | Increased expression of IL-1β, IL-6, TNFα, VEGF in synoviocytes |
Stannus O. et al. [19] | Follow-up study of serum cytokines in an elderly cohort | Quartiles of IL-6 and TNF-α are associated with joint space narrowing | Baseline and changes of IL-6 predicts medial and lateral cartilage volume loss |
Barker T. et al. [20] | Comparative study of serum IL-10 and TNF-α in different OA stages and controls | ↓ IL-10 and IL-10/TNFα in subjects who underwent ACL or TJR surgery No significant changes in TNFα | IL-10 and IL-10/TNFα significantly differ between Kellgren–Lawrence scores 3 vs. 4 Low IL-10 suggests predisposition for development of severe knee OA |
Panina S.B. et al. [21] | Comparative study of plasma and SF mediators in post-traumatic OA patients and controls | ↑ plasma leptin, IL-1β and IL-6 | Plasma leptin and SF IL-18 correlate with the Kellgren–Lawrence score in PTOA Significant correlation between plasma and SF leptin, IL-6 and IL-18 |
Waszczykowski M. et al. [22] | Comparative study of serum and SF cytokines in OA vs. healthy controls | ↑ serum IL-6, IL-18 and IL-20 in OA vs. control group | IL-18 correlates with MMP-3 in OA patients ROC curve of IL-20 suggests diagnostic potential |
Histological markers of inflammation | |||
Wang Z.W. et al. [14] | Synovial membrane immunohistochemistry analysis | ↑ IL-1β, IL-6, TNF-α and VEGF synovial membrane expression in moderate/advanced OA compared to mild OA | ↑ serum IL-1β, IL-6, TNFα, VEGF in OA patients vs. controls |
Qu X.Q. et al. [25] | Comparative genetic and immunohistochemistry study of OA vs. normal cartilage specimens (knee arthroplasty and meniscus surgery) | ↑ IL-6 and MMP-9 expression in OA specimens | ↑ IL-6 and MMP-9 gene expression in OA cartilage |
Warner S.C. et al. [27] | Immunohistochemistry and explant culture studies of OA patients | ↑ IL-15Rα in OA samples | IL-15 treatment induction of MMP-1 and MMP-3 |
Scanzello C.R. et al. [28] | Synovial membrane immunohistochemistry in early vs. advanced OA patient cohort | ↑ IL-15Rα in synovial membrane cells from patients with advanced OA | Increased IL-15 in SF, correlating with IL-6 |
Iannone F. et al. [29] | Comparative immunohistochemistry study of OA vs. healthy subjects | ↑ IL-10 protein and mRNA expression in high-intensity cartilage lesions | No relationship between IL-10R expression and cartilage lesion degree |
Vuolteenaho et al. [34] | OA patients cohort study of phenotype-explanted cartilage | ↑ IL-6, IL-8, PGE2, Cox-2 expression in cartilage cultures obtained by joint replacement, induced by leptin/IL-1β | Selective inhibition of iNOS suppressed IL-6, IL-8, PGE2 |
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Horváth, E.; Sólyom, Á.; Székely, J.; Nagy, E.E.; Popoviciu, H. Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis. Int. J. Mol. Sci. 2023, 24, 16468. https://doi.org/10.3390/ijms242216468
Horváth E, Sólyom Á, Székely J, Nagy EE, Popoviciu H. Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis. International Journal of Molecular Sciences. 2023; 24(22):16468. https://doi.org/10.3390/ijms242216468
Chicago/Turabian StyleHorváth, Emőke, Árpád Sólyom, János Székely, Előd Ernő Nagy, and Horațiu Popoviciu. 2023. "Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis" International Journal of Molecular Sciences 24, no. 22: 16468. https://doi.org/10.3390/ijms242216468