Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research
Abstract
:1. Introduction
2. IVD Extracellular Matrix in Health and Disease
2.1. Proteoglycans
2.2. Collagen
2.3. Water
3. IVD Cell Activity and Molecular Biology in Health and Disease
3.1. Multifactorial Regulation of Cell Activity in Health
3.2. Multifactorial Regulation of Cell Activity in Disease
4. IVD Regeneration Strategies: Biological Targets and Biomaterials
4.1. Signaling Pathways and Biological Targets
- ERK activation typically occurs via mitogens and GF (e.g., platelet-derived growth factor (PDGF), transforming growth factors β1 and β3 (TGF-β1, TGF-β3), fibroblast growth factor (FGF), and insulin-like growth factor (IGF) I [242,243,244]), thereby controlling growth, differentiation, cell cycle progression, and development. In addition, ERK activation in the IVD supports cell survival following hypoxia and osmotic stress, the latter with cross talk to TonEBP [118,119,120,121,245,246,247]. Interestingly, NP-derived mesenchymal stromal cells (MSC) also respond to osmotic stimuli, whereby hyperosmotic stress was associated with ERK activation, leading to a reduction in proliferation and chondrogenic differentiation [248]. Interestingly, excessive cyclic stretch was shown to induce AF apoptosis via inhibition of ERK phosphorylation, whereby β1 integrin could inhibit the apoptotic processes [249]. Pro-inflammatory cytokines, such as TNF-α and IL-1β, as well as stimuli known to induce inflammation, such as ECM fragments, activate the ERK pathway in IVD cells, possibly mediating loss of tissue ECM proteins associated with DD [31,55,250,251,252,253], inflammatory and catabolic responses [250,254,255], apoptosis [256], and senescence [257]. Interestingly, ERK was suppressed by stimulation with the anti-inflammatory cytokine IL-10 [254]. Overall, these findings indicate that modulating ERK activity for therapeutic means is possible yet challenging due to the multifactorial role of this signaling pathway.
- The p38 signaling pathway is generally activated by stressors and is known to regulate inflammation, autophagy, apoptosis, and differentiation [241]. Numerous studies have investigated p38 in the IVD, thereby identifying hypoxia [245], hyperosmolarity [120], hyperphysiological mechanical loads [133], ER stress [258], acidity [257], high glucose levels [256], and IL-1 [253] as potent activators. Interestingly, p38 is connected to TPRV4 [133], which has previously been described to transduce mechanical, inflammatory, and pain signals in cartilage [259]. Different research fields have shown extensive cross talk between p38 and other signaling pathways, e.g., ERK [258], TGF-β/Smad, [260] or Akt [261], which should be investigated in IVD cells. Overall, inhibition of p38 is being discussed for therapeutic approaches, potentially reducing inflammation, pain, and disc matrix catabolism [253,262], although ultimate outcomes may be difficult to predict due to the extensive cross talk with other pathways.
- JNK, similar to p38, is activated by stressors, GF, and pro-inflammatory cytokines [241,253]. Stressors entail high glucose levels [256], hyperosmolarity [120,263], TNF-α and IL-1β exposure [250,251,255], syndecan-4 overexpression [264], and Propionibacterium acnes (P. acnes) infection [265]. Following activation, JNK regulates apoptosis [120,256,265], enhanced expression of MMP [250], DNA damage [263], and DD [264]. The pro-apoptotic mechanisms of JNK seem to be associated with p53 induction [266] and with toll-like receptor 2 activation [265]. Although not yet investigated in the IVD, the interaction of JNK with miRNAs (e.g., miR-138, miR-133a-3p, miR-133b-3p, miR-4268) is likely relevant [267,268,269]. Therefore, a better understanding of JNK signaling will be needed before its modulation can be effectively used as a therapeutic means.
4.2. Growth Factor-Based Strategies
4.3. Cell Therapy-Based Strategies
4.4. Biomaterials and Nanotechnologies
5. Systems’ Modeling for the Exploration of IVD Degenerative and Regenerative Mechanisms
5.1. Organ- and Tissue-Scale Simulations of the IVD Biophysical Regulation
5.2. IVD Cell Models and Integration of Experimental Cell Stimulation Data
5.3. Cell Signalling Pathway Models and Integration of Multi-Omics Data
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ADAMTS | A disintegrin and metalloproteinase with thrombospondin motifs |
AF | Annulus fibrosus |
BMP | Bone morphogenetic protein |
CEP | Cartilage edplate |
DD | IVD degeneration |
ECM | Extracellular matrix |
ER | Endoplasmatic recticulum |
ERK | Extracellular signal-regulated kinase |
FA | Focal adhesion |
FGF | Fibroblast growth factor |
GAG | Glycosaminoglycan |
GDF | Growth differentiation factor |
GF | Growth factor |
HIF | Hypoxia inducible factor |
IGF | Insulin-like growth factor |
IL | Interleukin |
IVD | Intervertebral disc |
JNK | c-Jun NH2terminal kinase |
LBP | Low back pain |
MAPK | Mitogen-activated protein kinase |
MMP | Metalloproteinase |
MP | Microparticle |
MSC | Mesenchymal stromal cell |
mTOR | Mammalian target of rapamycin |
NF-κB | Nuclear factor kappa B |
NGF | Nerve growth factor |
NP | Nucleus pulposus |
p38 | p38 MAPK |
PCL | Poly-ε-caprolactone |
PDGF | Platelet-derived growth factor |
PDLLA | Poly D,L-lactide |
PEG | Polyethylene glycol |
PG | Proteoglycan |
PGA | Polyglycolic acid |
PKN | Prior-knowledge-network |
PLGA | Polylactic-co-glycolic acid |
PNIPAM | Poly N-isopropylacrylamide |
PU | Polyurethane |
TE | Tissue engineering |
TGF | Transforming growth factor |
TNF-α | Tumor necrosis factor alpha |
TonEBP | Tonicity-responsive enhancer binding protein |
TonEBP/NFAT5 | Tonicity-responsive enhancer binding protein/nuclear factor of activated T-cells 5 |
TRP | Transient receptor potential |
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Hydrogels for IVD TE | ||
---|---|---|
Natural Hydrogels | ||
Type | Material Biomechanical Properties | IVD Studies |
Alginate |
| |
Fibrin |
| |
Collagen |
|
|
Atelo-collagen |
|
|
Chitosan | ||
Gellan gum |
|
|
Hyaluronan (hyaluronic acid) |
| |
Synthetic Hydrogels | ||
Type | Material Biomechanical Properties | IVD Studies |
Poly N-isopropyl-acrylamide (pNIPAM)-based hydrogels | Laponite crosslinked pNIPAM-co-DMAc: | |
|
| |
HA-pNIPAM hydrogel: | ||
|
| |
Polyethylene glycol (PEG)-based hydrogels | Composites:
| |
Polyvinyl alcohol (PVA)-based hydrogels |
|
|
Self-assembling peptide hydrogels (SAPH) |
|
|
Scaffolds for IVD TE | ||
Natural Polymers | ||
Type | Material Biomechanical Properties | IVD Studies |
Silk fibroin |
|
|
Alginate | Composites: | |
Atelo- collagen |
|
|
Synthetic Polymers | ||
Type | Material biological and mechanical properties | IVD Studies |
Poly-urethane (PU) |
|
|
Polylactic acid polyglycolic acid (PGA) Copolymer: polylactic-co-glycolic acid (PLGA) |
|
|
Poly D,L-lactide (PDLLA) |
| |
Poly-ε-caprolactone (PCL) |
|
|
Title | Content | Size | Address |
---|---|---|---|
KEGG | Integrated database resource consisting of 18 databases including systems, genomic, chemical, and health information on the molecular interaction networks in biological systems | KEGG Pathway: 536 pathways | https://www.genome.jp/kegg/ [466] |
Reactome | Pathway database with interactive web visualization tool | 2272 pathways, 10,833 proteins, 12,505 interactions | https://reactome.org/ [467] |
STRING | Protein–protein interaction networks | 5000 organisms, 24.6 mio proteins, >2000 mio interactions | https://string-db.org/ [468] |
WikiPathways | Pathways of different species stored in wiki format | 2785 pathways, 28 species | https://wikipathways.org/ [469] |
Pathway Commons | Biological pathway data extracted from various databases with visualization tool | 4700 pathways, 2.3 mio interactions | https://pathwaycommons.org/ [470] |
Omnipath | Literature-curated mammalian signaling pathways from >50 databases | 10,934 proteins, 53,542 interactions | http://omnipathdb.org/[471] |
MatrixDB | Database focused on interactions established by extracellular matrix proteins, PG and polysaccharides | 106,453 associations from 38,921 experiments | http://matrixdb.univ-lyon1.fr/ [472] |
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Baumgartner, L.; Wuertz-Kozak, K.; Le Maitre, C.L.; Wignall, F.; Richardson, S.M.; Hoyland, J.; Ruiz Wills, C.; González Ballester, M.A.; Neidlin, M.; Alexopoulos, L.G.; et al. Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research. Int. J. Mol. Sci. 2021, 22, 703. https://doi.org/10.3390/ijms22020703
Baumgartner L, Wuertz-Kozak K, Le Maitre CL, Wignall F, Richardson SM, Hoyland J, Ruiz Wills C, González Ballester MA, Neidlin M, Alexopoulos LG, et al. Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research. International Journal of Molecular Sciences. 2021; 22(2):703. https://doi.org/10.3390/ijms22020703
Chicago/Turabian StyleBaumgartner, Laura, Karin Wuertz-Kozak, Christine L. Le Maitre, Francis Wignall, Stephen M. Richardson, Judith Hoyland, Carlos Ruiz Wills, Miguel A. González Ballester, Michael Neidlin, Leonidas G. Alexopoulos, and et al. 2021. "Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research" International Journal of Molecular Sciences 22, no. 2: 703. https://doi.org/10.3390/ijms22020703