issls prize winner: lumbar vertebral endplate lesions: associations with disc degeneration and back...
TRANSCRIPT
e53176.
364 Journal Reports / The Spine Journal 13 (2013) 363–365
of five cohorts of Northern European extraction each having GWA data im-
puted to HapMap V.2.
RESULTS: This study of 4600 individuals identified four single nucleo-
tide polymorphisms with p!5�10(–8), the threshold set for genome-wide
significance. We identified a variant in the PARK2 gene (p52.8�10(–8))
associated with LDD. Differential methylation at one CpG island of the
PARK2 promoter was observed in a small subset of subjects
(b58.74�10(–4), p5.006).
CONCLUSIONS: LDD accounts for a considerable proportion of low
back pain and the pathogenesis of LDD is poorly understood. This work
provides evidence of association of the PARK2 gene and suggests that
methylation of the PARK2 promoter may influence degeneration of the in-
tervertebral disc. This gene has not previously been considered a candidate
in LDD and further functional work is needed on this hitherto unsuspected
pathway.
PMID: 22993228 [PubMed - as supplied by publisher. Available at: http://
www.ncbi.nlm.nih.gov/pubmed/22993228].
Reprinted from: Williams FM, Bansal AT, van Meurs JB, et al. Novel ge-
netic variants associated with lumbar disc degeneration in northern Euro-
peans: a meta-analysis of 4600 subjects. Ann Rheum Dis 2012 Oct 17.
[Epub ahead of print].
http://dx.doi.org/10.1016/j.spinee.2013.02.021
ISSLS prize winner: Lumbar vertebral endplate lesions: associations
with disc degeneration and back pain history. Wang Y, Videman T,
Batti�e MC. Spine (Phila Pa 1976) 2012;37(17):1490–6.
STUDY DESIGN: An autopsy study.
OBJECTIVE: To investigate associations between various types of lum-
bar endplate lesions, disc degeneration (DD), and back pain history.
SUMMARY OF BACKGROUND DATA: The well-innervated vertebral
endplate has been suspected as a source of back pain. Previously, we ob-
served 4 types of lumbar endplate lesions with distinct morphological char-
acteristics. Their roles in DD and back pain remain unclear.
METHODS: From a lumbar spine archive of 136 men (mean age, 52 yr),
back pain, back injury, and occupation history data for 69 subjects and dis-
cography data for 443 discs from 109 subjects were available for study.
Back pain history was categorized as none, occasional, or frequent. DD
was judged from discography. Endplate lesions were classified as
Schmorl’s nodes, fracture, erosion, or calcification, and lesion size was
rated as none, small, moderate, or large. Associations between endplate le-
sions and DD, back pain history, back injury, and occupation history were
examined.
RESULTS: Presence of endplate lesions was associated with frequent
(odds ratio [OR]52.57) but not occasional back pain. However, large end-
plate lesions were associated with both occasional (OR58.68) and fre-
quent (OR517.88) back pain. This association remained after further
controlling for DD. Also, the presence of each type of endplate lesion
was associated with adjacent DD (OR52.40-9.71), with larger lesions as-
sociated with more severe DD. Endplate erosion lesions were more
strongly associated with adjacent DD than Schmorl’s nodes. Although
back injury history was associated with the presence of fracture and ero-
sion lesions, heavy occupation was associated with the presence of
Schmorl’s nodes.
CONCLUSION: Endplate lesions are associated with back pain as well as
being closely associated with adjacent DD, with a clear dosage effect. Dif-
ferent types of endplate lesions seem to have different magnitudes of asso-
ciations with DD. Lumbar endplate lesions may be an important key to
better understand both DD and back pain.
PMID: 22648031 [PubMed - indexed for MEDLINE. Available at: http://
www.ncbi.nlm.nih.gov/pubmed/22648031].
Reprinted with permission from: Wang Y, Videman T, Batti�e MC. ISSLS
prize winner: Lumbar vertebral endplate lesions: associations with disc
degeneration and back pain history. Spine (Phila Pa 1976)
2012;37(17):1490–6.
http://dx.doi.org/10.1016/j.spinee.2013.02.022
Leptin induces cyclin D1 expression and proliferation of human
nucleus pulposus cells via JAK/STAT, PI3K/Akt and MEK/ERK
pathways. Li Z, Shen J, Wu WK, et al. PLoS One 2012;7(12):
Increasing evidence suggests that obesity and aberrant proliferation of nu-
cleus pulposus (NP) cells are associated with intervertebral disc degener-
ation. Leptin, a hormone with increased circulating level in obesity, has
been shown to stimulate cell proliferation in a tissue-dependent manner.
Nevertheless, the effect of leptin on the proliferation of human NP cells
has not yet been demonstrated. Here, we show that leptin induced the pro-
liferation of primary cultured human NP cells, which expressed the leptin
receptors OBRa and OBRb. Induction of NP cell proliferation was con-
firmed by CCK8 assay and immunocytochemistry and Real-time PCR
for PCNA and Ki-67. Mechanistically, leptin induced the phosphorylation
of STAT3, Akt and ERK1/2 accompanied by the upregulation of cyclin D1.
Pharmacological inhibition of JAK/STAT3, PI3K/Akt or MEK/ERK sig-
naling by AG490, Wortmannin or U0126, respectively, reduced leptin-
induced cyclin D1 expression and NP cell proliferation. These experiments
also revealed an intricate crosstalk among these signaling pathways in me-
diating the action of leptin. Taken together, we show that leptin induces
human NP cell cyclin D1 expression and proliferation via activation of
JAK/STAT3, PI3K/Akt or MEK/ERK signaling. Our findings may provide
a novel molecular mechanism that explains the association between obe-
sity and intervertebral disc degeneration.
PMID: 23300886 [PubMed - in process. Available at: http://www.ncbi.
nlm.nih.gov/pubmed/23300886].
Reprinted from: Li Z, Shen J, Wu WK, et al. Leptin induces cyclin D1
expression and proliferation of human nucleus pulposus cells via JAK/
STAT, PI3K/Akt and MEK/ERK pathways. PLoS One 2012;7(12):
e53176.
http://dx.doi.org/10.1016/j.spinee.2013.02.023
Genotoxic stress accelerates age-associated degenerative changes in
intervertebral discs. Nasto LA, Wang D, Robinson AR, et al. Mech
Ageing Dev 2013;134(1–2):35–42. Epub 2012 Dec 19.
Intervertebral disc degeneration (IDD) is the leading cause of debilitating
spinal disorders such as chronic lower back pain. Aging is the greatest risk
factor for IDD. Previously, we demonstrated IDD in a murine model of
a progeroid syndrome caused by reduced expression of a key DNA repair
enzyme. This led us to hypothesize that DNA damage promotes IDD. To
test our hypothesis, we chronically exposed adult wild-type (Wt) and
DNA repair-deficient Ercc1(-/D) mice to the cancer therapeutic agent
mechlorethamine (MEC) or ionization radiation (IR) to induce DNA dam-
age and measured the impact on disc structure. Proteoglycan, a major
structural matrix constituent of the disc, was reduced 3–5� in the discs
of MEC- and IR-exposed animals compared to untreated controls. Expres-
sion of the protease ADAMTS4 and aggrecan proteolytic fragments was
significantly increased. Additionally, new PG synthesis was reduced
2–3� in MEC- and IR-treated discs compared to untreated controls. Both
cellular senescence and apoptosis were increased in discs of treated ani-
mals. The effects were more severe in the DNA repair-deficient Ercc1
(-/D) mice than in Wt littermates. Local irradiation of the vertebra in Wt