Table 1.

Main IVD microenvironment features under physiological and degenerative conditions.

	Healthy IVD	IDD
Avascularity	Vessels from the vertebral bodies branch into capillaries terminating in the CEP [21]	CEP calcification may hinder nutrient diffusion [39]
Hypoxia	Oxygen concentration decreases from AF surfaces (19.5%) to the inner portion of the NP (0.65%) [40]	Oxygen concentration falls due to reduced blood supply and shift of NP cell metabolism towards oxidative phosphorylation [41]
Low glucose concentration	Glucose concentration is higher at IVD boundaries while it falls towards the center of the NP [42]	Glucose levels diminish together with blood supply and increased consumption by degenerative cells [43]
Acidity	Due to anaerobic glycolysis and lactic acid production, average pH is 7.0-7.2 [38]	pH may decrease to 6.5 in mild IDD and 5.6 in severe IDD due to nutrient depletion and increase lactic acid production [38]
Hyperosmolarity	The high GAG content within the NP determines a high osmolarity which varies upon mechanical load (430-500 mOsm/L) [44]	The loss of proteoglycans due to matrix breakdown reduces IVD osmolarity [45]
Mechanical loading	Mechanical stimuli (flexion, torsion, shear, and compression) regulate IVD cell activity and metabolism within a physiological range (0.1-2.5 MPa) [46, 47]	Disruption of IVD structure alters loading transmission across the IVD and the vertebral segments, resulting in tissue damage and cellular overstress [48]
Inflammation	Proinflammatory cytokines and chemokines may have a role in IVD development and recruitment of local progenitor cells [49, 50]	The excess of proinflammatory cytokines increases cell apoptosis, senescence, autophagy, matrix breakdown, and discogenic LBP [51]

CEP = cartilaginous end plate; AF = annulus fibrosus; NP = nucleus pulposus; IVD = intervertebral disc; IDD = intervertebral disc degeneration; GAG = glycosaminoglycan; LBP = low back pain.