Table 2.
Main characteristics of osteokines modulating IVD homeostasis and degeneration.
| Organokines (Receptors) |
Target | Model | Signaling pathway |
Cellular behavior or phenotype induced by organokines | Citation |
|---|---|---|---|---|---|
| OPG (RANK/RANKL) |
Disc cell | Exposurea | RANKL↓ | Inflammation (IL-1β)↑; Catabolism (MMP-3, 13)↑ | (62–64) |
| CEP | OPG KOb | NA | Inflammation (IL-1β, IL-6, TNF-α)↑; Tissue remodeling (TRAP, Rank, MMP-9, Cathepsin K)↑; Chondrogenesis (cartilage area, growth plate thickness, aggrecan)↑; Neovascularization (VEGF-A, CD31, VE-cadherin, CD34)↑; |
(65–67) | |
| Sclerostin (LRPs) |
NP | Sost KOb; Exposureb |
Wnt/β-catenin↑ | Matrix maturation (Col II, FOXA2, Osterix)↑; DDK-1↓; Matrix stiffness (proteoglycan↓; hydration↓)↑; DHI↓ |
(68) |
| PTHrP (PTH-1R) |
NPC AFC |
Analogue (PTH)a | mTOR↑; MAPK↑; PKA↑ | Autophagy (Beclin-1, p62, LC3B)↑; Senescence (SA-β-gal)↓; Matrix mineralization (Acan↑, Col I↑, COLX↓, calcium release↓)↓ |
(69, 70) |
| NPC CEP |
Analogue (PTH)a,b | Wnt/β-catenin↑ | Anabolism (Acan, Col II)↑; Catabolism (MMP3, 9)↓; Tissue remodeling (endplates calcification↓; micro-vessel density↓, porosity↑, thickness↑)↑; Histological score↓; DHI↑ |
(71, 72) | |
| NPC NP | Analogue (PTH)a,b | CREB/Sonic Hedgehog↑ | Oxidative stress (SOD-1, 2)↓; Apoptosis (Caspase-3, 8, 9)↓; Inflammation (IL-1β, IL-6, TNF-α)↓ |
(73) | |
| IVD | PTH1R KOb; Analogue (PTH)b |
Integrin αvβ6/TGF-β/CCN2↑ | IVD volume↑; IVD height↑; MRI signal intensity↑ | (74) | |
| BMP-2,7 (BMPR-I/II) |
NPC AFC NP |
Exposureab; KDa |
PI3K/Akt↑; Puma↓ |
Apoptosis (Apaf-1, cleaved-caspase-3,9)↓; Senescence (SA-β-Gal, G0/G1 arrest, p16, p53)↓; Inflammation (IL-6 and TNF-α)↓; Anabolism (Acan, Col II, SOX-9)↑; Catabolism(MMP-13)↓; DHI↑; |
(75–77) |
| Osteonectin/SPARC (CXCR1/2, TLR-4) |
NP | SPARC KOb | NA | Inflammation (CXCL-1, 5)↓; Macrophage activation (ITGAM↓)↑; Endplate calcification↑; DHI↓ |
(78, 79) |
| NP | SPARC KOb; Receptor inhibitiona |
NA | Inflammation (C3aR1, COX-2, CCL-7,19)↓; Catabolism (MMP-3, 13↓, TIMP1, 2↑)↓; Neutral zone stiffness↓; |
(80) |
↑, increase; ↓, decrease; NA, not available; Exposurea, exposure in vitro; Exposureb, exposure in vivo; KDa, konock down in vitro; KDb, knock down in vivo; KOb, knock out in vivo; Receptor activationa, receptor activation in vitro; Receptor activationb, receptor activation in vivo; RANK, receptor activator of NF-κB; RANKL, receptor activator of NF-κB ligand; PTH, parathyroid hormone; PTH1R, parathyroid hormone type 1 receptor; BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; SPARC, secreted protein acidic and rich in cysteine; TRAP, tartrate-resistant acid phosphatase type 5; VEGF-A, vascular endothelial growth factor-A; VE-cadherin, vascular endothelial-cadherin; FOXA2, forkhead box protein a2; SOD, superoxide dismutase; CCN2, communication network factor-2; Apaf-1, apoptotic protease activating factor-1; CXCL, C-X-C motif ligand; ITGAM, integrin subunit alpha M; C3aR1, complement 3a receptor 1; TIMP,tissue inhibitor of matrix metalloproteinase.