Intervertebral Disc Aging, Degeneration, and Associated Potential Molecular Mechanisms-Juniper publishers
JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF HEAD NECK & SPINE SURGERY
Abstract
Intervertebral disc degeneration is a major cause of
neck and back pain, a very common clinical problem. However, no
effective treatment is available, which is largely due to the lack of
understanding of molecular mechanisms underlying disc degeneration.
Here, we briefly described the process of intervertebral disc aging and
degeneration and summarized major findings in molecular signaling
pathways implicated in disc aging and degeneration.
Mini Review
An intervertebral disc consists of an annulus
fibrosus ring, a nucleus pulposus core, and two cartilaginous superior
and inferior endplates. The outer annulus is made up of highly ordered
collagen lamellae in which type I collagen fibers are aligned with
elongated fibroblasts [1,2].
Relative to the outer annulus, the inner annulus is more like
cartilage, containing spherical chondrocyte-like cells, and greater
amount of type II collagen and proteoglycans [3].
The central nucleus, a highly hydrated gelatinous tissue, is
predominantly composed of proteoglycans produced by large notochordal
cells [4].
The annulus, the nucleus, and the endplates are interconnected to form
the most important part of the motion segment of the spine, allowing the
intervertebral disc to function as a shock absorber and to resist
tensile and torsional forces. Human disc degeneration starts during
childhood. As notochordal cells diminish rapidly after birth and are
gradually replaced by much smaller chondrocytes, the nucleus becomes
dehydrated and cartilagelike by adulthood [5].
In the early stage of disc degeneration, clefts and tears occur in the
nucleus and the inner annulus, and chondrocyte-like cells in the inner
annulus proliferate (cloning) and produce matrix in the vicinity of the
structural defects [6].
However, the regenerated tissue cannot withstand the daily loading of
the spine, leading to structural defect progression. As disc
degeneration advances, clefts/tears extend into the outer annulus, and
are filled with granular material; fibroblasts in the outer annulus
differentiate into chondrocyte-like cells, and deposit matrix;
chondrocyte-like cells in the inner annulus and endplates form large
clones and migrate into the nucleus [6,7].
In the late stage of disc degeneration, collagen content and cross
linking increase throughout the disc; the distinction between the
anatomic regions is no longer possible; and the entire disc becomes
fibrotic and scar-like [6,8].
As described above, disc degeneration is an
age-related process. Thus, it is difficult to distinguish the
physiologic process of disc aging from that of disc degeneration. In
general, when a disc with structural failure is combined with
accelerated or advanced signs of aging, it is considered to be a
degenerate disc [8,9].
Given that the process of disc aging is affected by many risk factors
such as genetic inheritance, excessive mechanical loading, obesity,
trauma, nutrition, smoking, and inflammation, as well as catabolic
cytokines and proteases, disc degeneration occurs in every population
worldwide [7].
It affects almost all individuals by sixth and seventh decade of life.
As disc degeneration is a major cause of neck and back pain, a leading
cause of disability in people aged less than 45 years, an effective
treatment is required [10,11].
Currently, this disease is firstly treated with conservative measures
for pain relief. If pain persists, surgical therapies include
decompression, spinal fusion and disc replacement will be performed.
However, all these treatment methods are not curative because none of
them can prevent, reverse or slow down the process of disc generation.
The lack of drugs that can effectively treat the neck and back pain
patients beyond pain relief is largely due to the lack of understanding
of the molecular mechanisms underlying disc degeneration.
Senescent cell accumulation in discs plays a central
role in disc aging and degeneration, because most risk factors are
senescence-inducing stresses and some are consequences of senescent
cells [12,13]. Senescent cells cease proliferation, but remain metabolically active and exhibit altered gene expression [14].
Since in human adult discs, blood vessels are normally restricted to
the outmost layers of the annulus, and the inner annulus and entire
nucleus are a vascular tissue, disc cells resident in these regions
experience a limited nutrition supply, hypoxia, anaerobic metabolism,
and associated increase in acidity. Accumulating evidence supports the
view that disc cells can tolerate this condition, otherwise the cells
die or become senescent. For example, when rat or bovine disc cells were
cultured at low oxygen (0-5% O2) levels, the cells were viable,
underwent proliferation and produced significant amount of
proteoglycans, whereas the normoxia (20-21% O2) level caused
decreased cell survival rate, reduced proteoglycan synthesis, and
enhanced expression of matrix metalloproteinases (MMPs) [15,16]. Disc cells are more sensitive to the concentrations of nutrients than O2.
Bovine disc cells would die or underwent senescence without glucose,
but enhanced proliferation and matrix synthesis in low glucose cultures [15,17].
However, if the cells were cultured under high glucose, a
glucose-mediated oxidative stress was generated and induced senescence [18].
Although permeability and metabolite transport decrease in an aging
disc due to low water content in the nucleus and fibrotic feature of
entire disc, they increase again when the aging disc is herniated or
injured due to trauma or repetitive overloading [19],
which presumably leads to an aberrant increase in concentrations of
nutrients in the microenvironment adjacent to the structural defects,
because cell cloning, senescent cells, and structural defect extension
are frequently detected in the areas adjacent to structural defects [9,20-22].
These phenotypic changes imply a correlation between cell
proliferation, cell senescence, and matrix breakdown during disc
degeneration progression. Consistently, senescent cell number in human
degenerative discs increases with advancing disc degenerative grade and
positively correlates with the expression levels of matrix-degrading
enzyme MMP-13 and aggrecanase ADAMTS-5 [23].
Cell senescence transition in human discs is most
likely induced via p53-p21-Rb pathway. Several lines of evidence suggest
that with advancing disc degenerative grade, senescent cell number is
increased, telomere lengthen is shortened, and p53-p21-Rb pathway is
actively maintained [21,23,24]. When disc cells were cultured in vitro, p16-Rb pathway was activated once the cells entered senescence program [25].
Although the risk factors for disc degeneration such as excessive
loading, trauma, nutrition, and smoking, etc. often induce acute
senescence transition in in vitro and in vivo models via p16-Rb pathway [15,16,18,26],
they may exert an effect individually or cumulatively on disc cells in
human beings via affecting the telomere-shortening-rate.
Smad ubiquitin regulatory factor (Smurf)2, an E3
ubiquitin ligase, was highly detected in human degenerated articular
cartilage, and over expression of Smurf2 under the control of type II
collagen alpha 1 promoter (Col2a1) induces osteoarthritis in Col2a1-Smurf2 transgenic mice [27]. We have recently shown that Col2a1-Smurf2 transgenic mice also exhibit accelerated age-related intervertebral disc degeneration [9].
During development of the disc degeneration in these transgenic mice,
many phenotypic changes such as fibroblast-to-chondrocyte
differentiation, chondrocyte-like cell cloning, migration, and fibrosis,
were similar to those occurring in humans and reflected connective
tissue growth factor (CTGF) function during wound healing and
scleroderma [28]. Indeed, CTGF expression and secretion is increased in the chondrocyte-like cells that are prone to degenerate in Col2a1-Smurf2 transgenic mouse discs, indicating that Smurf2-mediated disc degeneration is via up regulation of CTGF [9].
Because discs possess a limited ability to repair when they are
disrupted, tears/clefts in discs are never healed and could cause a
persistence of CTGF expression by the cells adjacent to the structural
defects due to continuous production and release of TGF-p, an inducer of
CTGF expression, by these cells as a cellular response to repetitive
excessive deformation of disrupted matrix [8,29,30] Wu et al. [31] (unpublished data). Notably, TGF-β induces Smurf2 expression in chondrocytes in vitro [31].
Thus, it is possible that in an aging disc, TGF-β activity is increased
in the microenvironment adjacent to structural defects activates Smurf2
gene expression by the local cells. Smurf2, in turn, induces disc
generation via up regulation of CTGF.
While Smurf2 was originally found to be an E3
ubiquitin ligase, which targets the TGF-β receptor and
receptor-regulated Smads for ubiquitination and proteasomal degradation [32,33], it was reported to induce cell senescence in cultured proliferating fibroblasts via activation of p53 pathway [34].
As the senescence associated secretory phenotype accompanies disc aging
and degeneration, we are testing a hypothesis that in Col2a1-Smurf2
transgenic mice, the disc chondrocyte-like cells that over express
Smurf2 could become senescent, and secrete CTGF, leading to disc
degeneration and progression.
Acknowledgments
This manuscript was supported by NIH/NINDS RO1 NS067435 (JH).
To know more about Open Access Journal of
Head Neck & Spine Surgery please click on:
Comments
Post a Comment