Genetics in Cartilage Lesions: Basic Science and Therapy Approaches
Abstract
:1. Introduction
2. Genetic Basis of Cartilage Pathology
3. Diagnostic and Therapeutic Biomarkers
3.1. Metalloproteinases
3.2. Growth Factors
3.3. Inflammatory Factors
4. Types of Genetic Changes
4.1. Single Nucleotide Polymorphisms
4.2. Epigenetic Changes
5. Gene Therapy Approaches
5.1. Marrow Stimulation
5.2. Autologous Chondrocyte Implantation
5.3. Muscle and Fat Grafts
5.4. Scaffolds
5.5. Mesenchymal Stem Cells
6. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Gene Category | Gene(s) | Therapeutic Potential | Ref. |
---|---|---|---|
extracellular matrix components | PIIANP, CTX-II, PIINP, COMP, type II collagen | inhibition of collagen and proteoglycan degradation, stimulation of cartilage matrix synthesis and/or cell proliferation | [13] |
matrix-degrading enzymes proteolytic enzymes | metalloproteinases (MMPs such as MMP-3, MMP-9 and MMP-13); aggrecanases (e.g., ADAMTS-4 or ADAMTS-5) and their inhibitors (TIMP-1, TIMP -2) | inhibition of ECM degradation | [14,15,16,17,18,19,20,21,22,23,24] |
circulating or locally occurring cytokines, inflammatory mediators and anabolic growth factors | TGF-β1,2,3; BMP-2,-4,-7; CDMP-1,-2,-3; IGF-1, PDGF, EGF, HGF | stimulation of chondrogenic differentiation, cartilage matrix synthesis, and/or cell proliferation | [25,26,27] |
inflammatory factors | IL-1Ra, IL-1R, ICE inhibitor, TNF-R, anti-TNF-antibodies, TACE inhibitor, TIMP-1,-2, MMP inhibitors, IL-4,-10,-11,-13 | anti-inflammatory mechanism: IL-1 blockage, TNF-α and MMPs inhibition | [21,28,29,30,31,32,33,34,35] |
transcription factors | Runx2, CEBPβ, HIF2α, Sox4, Sox9, and Sox11 | stimulation of chondrogenic differentiation | [36,37,38,39,40] |
growth factors and signal transduction molecules | PTHrP, IHH, SHH, DHH, Smad 6, -7, mLAP-1 | inhibition of osteogenesis/hypertrophy, TGF-β/BMP action, and terminal differentiation | [41,42,43,44,45,46] |
apoptosis regulators | Bcl-2, Bcl-XL, Anti-FasL, Akt, PI3-kinase, NF-κB | apoptosis inhibition: caspase inhibition, FAS-l blockage no-induced apoptosis, TNF-α and trail inhibition | [47,48,49,50] |
Gene | SNPs | Affected Joint and Impact | Reference |
---|---|---|---|
MMP-3 | rs639752, rs520540, rs602128, rs650108, rs679620 |
| [73,114] |
MMP-8 | rs1940475, rs3765620 |
| [115] |
TIMP-3 | rs715572 (G/A), rs1962223 (G/C) |
| [114,116] |
COL11A1 | rs1241164, rs4907986, rs2615977 |
| [117] |
COL9A2 | rs7533552 |
| [118] |
VEGF | rs833058 |
| [117] |
DVWA | rs7639618, rs9864422, rs11718863 |
| [119,120,121] |
FRZB | rs7775, rs288326 |
| [122,123] |
GDF5 | rs143383 (risk allele T) |
| [123,124] |
CALM1 | rs12885713 (-16C/T transition SNP) |
| [125,126,127,128] |
TGF-1β | rs1982073, rs1800470 (TT genotype), rs180046 (TT genotype and T allele), rs1800469 (TT genotype and T allele) |
| [116,129] |
IGF1 | rs2195239, rs11247361 (4488C>G) |
| [130,131,132,133] |
IL1RN | rs9005, rs315952, rs419598, rs315943, rs315920 (C/t) |
| [134,135,136,137,138,139] |
IL-6 | rs1800795 (−174G>C) |
| [132,140] |
MCF2L | rs11842874 (risk allele G) |
| [141,142,143] |
SMAD3 | rs12901499 (GA and GG genotypes), rs12102171 (CC and CT+TT and TT and TG+GG), rs2289263, rs6494629 (T/C), |
| [116,144,145] |
BMP5 | rs921126 (GA and GG genotypes) |
| [145] |
ADAM12 | rs1871054, rs3740199 (Gly48Arg) |
| [132,146] |
ADAMTS14 | rs4747096 |
| [147,148,149,150] |
Gene(s) | Vector(s) | Scaffold | Reference |
---|---|---|---|
Sox9 | rAAV | polymeric micelles | [211] |
rAAV | poloxamers, poloxamines, micellar systems | [211] | |
IL-1Ra | lentiviral | poly-e-caprolactone | [202,205,209] |
lacZ | rAAV | poloxamers, poloxamines, micellar systems | [207] |
rAAV | alginate, alginate/poloxamers | [212] | |
rAAV | polypseudorotaxane gels | [213] | |
TGF-β1 | rAAV | poloxamers, poloxamines, micellar systems | [214] |
lentiviral | poly-e-caprolactone | [215] | |
rAAV | polymeric micelles | [214] | |
IL1RN and IGF1 | non-viral | chitosan | [216] |
lacZ, RFP | rAAV | self-assembling peptide hydrogels | [212,217] |
lacZ, RFP, Sox9 | rAAV | poloxamers, poloxamines, micellar systems | [213,218] |
Sox9, TGF-β | rAAV | carbon dots | [219] |
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Szwedowski, D.; Szczepanek, J.; Paczesny, Ł.; Pękała, P.; Zabrzyński, J.; Kruczyński, J. Genetics in Cartilage Lesions: Basic Science and Therapy Approaches. Int. J. Mol. Sci. 2020, 21, 5430. https://doi.org/10.3390/ijms21155430
Szwedowski D, Szczepanek J, Paczesny Ł, Pękała P, Zabrzyński J, Kruczyński J. Genetics in Cartilage Lesions: Basic Science and Therapy Approaches. International Journal of Molecular Sciences. 2020; 21(15):5430. https://doi.org/10.3390/ijms21155430
Chicago/Turabian StyleSzwedowski, Dawid, Joanna Szczepanek, Łukasz Paczesny, Przemysław Pękała, Jan Zabrzyński, and Jacek Kruczyński. 2020. "Genetics in Cartilage Lesions: Basic Science and Therapy Approaches" International Journal of Molecular Sciences 21, no. 15: 5430. https://doi.org/10.3390/ijms21155430