Biomedical Engineering Reference
In-Depth Information
5
Intervertebral Disc Degeneration
IDD is an aberrant cell-mediated process driven by a multitude of contributing
factors including disc nutrition, mechanical forces, and genetics. The interplay of
these elements culminates in detrimental changes within the disc's ECM. Histolog-
ical evidence suggests that alterations in IVD ECM biochemistry appear to initiate
within the end-plates and NP as early as 11-16 years of age [ 31 ]. Together, these
changes eventuate in the discs' structural and functional demise and result in
downstream effects on adjacent spinal structures, spinal biomechanics, and pain
generation.
During degeneration, a number of changes in the biochemistry of the IVD are
observed: disc water content and aggregating proteoglycan content decrease, non-
enzymatic crosslinking of type II collagen occurs inhibiting matrix turnover and
repair, and the production of proteoglycan decreases concomitant with a shift from
chondroitin sulfate-rich aggrecan to a keratin sulfate-substituted version [ 14 , 16 , 21 ,
32 - 34 ]. Additionally, overall matrix degradation, in particular aggrecan and colla-
gen type II, has been shown to increase in the degenerating IVD [ 35 ]. Increased
fragmentation of aggrecan has been shown to occur, which may ultimately lead to
glycosaminoglycan leaching and reduced osmotic pressure within the NP [ 32 , 36 ].
Although disc collagen content does not significantly change with degeneration,
fibrillar collagens (especially type II collagen) become more fragmented and their
spatial distribution changes. This is particularly evident in the NP, which becomes
infiltrated with collagen type I with increasing degeneration [ 35 , 37 ]. IVD fibro-
nectin content increases and becomes more fragmented with degeneration as well
[ 38 ]. Interestingly, fragments of both collagen type II and fibronectin have
exhibited the ability to perpetuate the degenerative cascade by upregulating MMP
activity, causing further degradation of type II collagen and aggrecan [ 38 - 40 ].
Current evidence suggests that the cells of the IVD are themselves the primary
culprits responsible for the destruction of the IVD ECM via the increased produc-
tion of numerous proteinases (Table 2 )[ 26 , 27 , 41 , 42 ]. In most cases, pro-
duction of tissue inhibitors of MMPs (TIMPs) increases in parallel with MMP
synthesis; however, TIMP-3 (an inhibitor of ADAMTS-4) may not, thus potentially
Table 2 Summary of the matrix metalloproteinases involved in intervertebral disc degeneration
[ 26 , 41 ]
Enzyme name
Synonym
Major substrate
MMP-1
Collagenase I (interstitial)
Fibrillar collagen (prefers type III)
MMP-2
72-kDa gelatinase A
Gelatins, fibronectins, elastins
MMP-3
Stromelysin-1
Aggrecan, fibronectins, gelatins
MMP-7
Matrilysin
Aggrecan, fibronectins, gelatins
MMP-8
Neutrophil collagenase
Fibrillar collagen (prefers type I), aggrecan
MMP-9
92-kDa gelatinase B
Gelatins
MMP-13
Collagenase III
Fibrillar collagens (prefers type I)
ADAMTS-4
Aggrecanase
Aggrecan core protein
ADAMTS-5
Aggrecanase
Aggrecan core protein
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