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