TABLE 3.

Illustrative examples of large and small animal models of IVD degeneration

Animal model	Degenerative mechanism	Features of model	Ref
24G needle stick AF lesion rat IVDD model	Elevation in TNFα, IL‐6 and NGF in injured IVD and increases in CGRP, Ca‐binding adaptor protein DRG GFAP	Persistent increases in pain neuropeptides in DRGs and spinal cord glia in the sensory dorsal root horns	228
Needle stick injury plus dynamic compression rat IVDD model Potential patho‐mechanism of LBP	Transient elevation in TNFα, IL‐1β, IL‐6 levels and IVDD, compression induces elevated neuropeptide levels in DRGs and SC dorsal horn	Increase in IVD inflammatory mediator levels. IVD injury/dynamic compression produces a long‐lasting inflammatory response and CGRP in DRGs/SC dorsal horn.	114 , 183
Rat bent tail sustained static compression model of IVDD Induces mild degeneration	Upregulation of MMPs and ADAMTSs and down regulation of TIMPs leads to ECM degradation and IVDD in C7‐C10 IVDs	Static IVD compression alters collagen and MMPs, induces IVDD and β1 integrin expression. Ilizarov device used on 7–10th caudal VBs	229 , 230 , 246
Murine tail IVDD (i) External tail IVD static compression device (ii) Mouse compressive suture model of IVDD	Compression of IVDs leads to reduced NP hydration, and a reduction in IVD type II collagen and aggrecan content.	IVDD is induced by increased compression on cells in the tail IVDs	247 , 248
Controlled IVD destabilization induced by a large AF lesion, modification of the Ovine Osti annular rim lesion model of IVDD.	Mechanical destabilization of the IVD using a controlled annular lesion increases MMP and ADAMTS expression by IVD cells, leading to degradation of type II collagen and aggrecan and a decrease in the biomechanical competence of the IVD.	IVDD impacts endplate vascularity, VB remodeling, degeneration of facet joint, neovascularization and nerve ingrowth into IVD. MSCs regenerate degenerate IVD. Reduces spinal flexibility, neuromuscular control of spinal muscle, multifidis muscle changes and LBP with IVDD.	37 , 38 , 39 , 40 , 41 , 42 , 43 , 104 , 249 , 250 , 251 , 252 , 253 , 254
Rabbit intermittent cyclic mechanical tension model elliciting damage to CEP.	CEP damage occurs via the Nuclear Factor‐κB cell signaling pathway and the up‐regulation of MMP‐13 to induce IVDD.	Cyclic mechanical tension induces CEP calcification, decreases type II collagen, aggrecan and Sox9 expression and impacts nutrition of IVD	231 , 232 , 233
Spontaneous IVDD models (i) Sand rat (ii) Chondrodystrophoid (ChD) canine (iii) non‐ChD canine (iv) SM/J Mouse	Age dependant reduction in PGs, IVD hydration, ECM biomechanical competence. Early IVDD in ChD canine compared to non‐ChD due to relative decline in notochordal cell numbers. SM/J mouse early onset spontaneous IVDD. NP cell death, degeneration of NP, AF, CEP. Elevated expression of Col10a1, Ctgf, Runx2 and chondrocyte hypertrophy.	Degeneration of NP & AF, osteophytosis, cell death, CEP sclerosis, decline in notochordal cells in sand rat and ChD canine. Non‐ChD canine has less IVDD. Prominent ARGxx Agg'ase neo‐epitope shows higher aggrecan turnover, abberant expression of collagen X and MMP‐13. High expression of Enpp1 and Alpl indicates increased dystrophic mineralization of CEP.	234 , 235 , 236 , 237 238 , 239 , 255 , 256 , 257 , 258 113
Rat multifidus resection Model of IVDD Murine paraspinal muscle surgical lesion IVDD model	Spinal destabilization	These IVDD models show the interdependence of spinal muscles and the IVD for the maintenance of spinal stability and efficient spinal weight bearing.	242 241
Evaluation of GDF‐6 in the attenuation pro‐inflammatory conditions on a rabbit AF puncture model of IVDD and pain generation in a rat xenograft radiculopathy model	Rabbit annular puncture induced biomechanical destabilization Rat xenograft radiculopathy model	Evaluation of GDF6 on: (i) gene expression of inflammatory/pain‐related molecules and structural integrity in a rabbit IVDD model, and (ii) sensory dysfunctional changes leading to pain‐marker expression in a rat DRG xenograft radiculopathy model.	243
Evaluation of the efficacy of GDF6 in a rat posterior disc puncture model conducted at a single and three consecutive IVD levels	Rat posterior annular puncture destabilization model of IVDD induced at a single and at three consecutive IVD levels	GDF6 lowers production of inflammatory mediators and pain peptides, improves IVD structural organization and benefits animal pain related behavior.	244