TY - JOUR
T1 - Effect of hyperglycemia on apoptosis of notochordal cells and intervertebral disc degeneration in diabetic rats
T2 - Laboratory investigation
AU - Won, Ho Yeon
AU - Park, Jong Beom
AU - Park, Eun Young
AU - Riew, K. Daniel
PY - 2009/12
Y1 - 2009/12
N2 - Object. Diabetes mellitus is thought to be an important etiologic factor in intervertebral disc degeneration. It is known that notochordal cells gradually disappear from the nucleus pulposus (NP) of the intervertebral disc with age by undergoing apoptosis. What is not known is whether diabetes has an effect on apoptotic rates of notochordal cells. The purpose of this study was to investigate the effect of hyperglycemia on apoptosis of notochordal cells and intervertebral disc degeneration in age-matched OLETF (diabetic) and LETO (control) rats. Methods. Lumbar disc tissue (L1-2 through L5-6), including cranial and caudal cartilaginous endplates, was obtained from 6- and 12-month-old OLETF and LETO rats (40 rats, 10 in each of the 4 groups). The authors examined the NP using TUNEL, histological analysis, and Western blot for expression of matrix metalloproteinase (MMP)-1, -2, -3, and -13, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, and Fas (apoptosis-related protein). The apoptosis index of notochordal cells was calculated. The degree of transition of notochordal NP to fibrocartilaginous NP was classified on a scale ranging from Grade 0 (no transition) to Grade 4 (transition > 75%). The degree of expression of MMP-1, -2, -3, and -13, TIMP-1 and -2, and Fas was evaluated by densitometry. Results. At 6 and 12 months of age, OLETF rats showed increased body weight and abnormal 2-hour glucose tolerance tests compared with LETO rats. The apoptosis index of notochordal cells was significantly higher in the OLETF rats than in the LETO rats at both 6 and 12 months of age. The degree of transition of notochordal NP to fibrocartilaginous NP was significantly higher in the OLETF rats than in the LETO rats at 6 and 12 months of age. The expression of MMP-1, -2, -3, and -13, TIMP-1, and Fas was higher in the OLETF rats at 6 and 12 months of age. The expression of TIMP-2 was significantly higher in the OLETF rats than in the LETO rats at 6 months of age, but not at 12. Conclusions. The findings suggest that diabetes is associated with premature, excessive apoptosis of NP notochordal cells. This results in an accelerated transition of a notochordal NP to a fibrocartilaginous NP, which leads to early intervertebral disc degeneration. It remains to be determined if these premature changes are due to hyperglycemia or some other factors associated with diabetes. Understanding the mechanism by which diabetes affects disc degeneration is the first step in designing therapeutic modalities to delay or prevent disc degeneration caused by diabetes mellitus.
AB - Object. Diabetes mellitus is thought to be an important etiologic factor in intervertebral disc degeneration. It is known that notochordal cells gradually disappear from the nucleus pulposus (NP) of the intervertebral disc with age by undergoing apoptosis. What is not known is whether diabetes has an effect on apoptotic rates of notochordal cells. The purpose of this study was to investigate the effect of hyperglycemia on apoptosis of notochordal cells and intervertebral disc degeneration in age-matched OLETF (diabetic) and LETO (control) rats. Methods. Lumbar disc tissue (L1-2 through L5-6), including cranial and caudal cartilaginous endplates, was obtained from 6- and 12-month-old OLETF and LETO rats (40 rats, 10 in each of the 4 groups). The authors examined the NP using TUNEL, histological analysis, and Western blot for expression of matrix metalloproteinase (MMP)-1, -2, -3, and -13, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, and Fas (apoptosis-related protein). The apoptosis index of notochordal cells was calculated. The degree of transition of notochordal NP to fibrocartilaginous NP was classified on a scale ranging from Grade 0 (no transition) to Grade 4 (transition > 75%). The degree of expression of MMP-1, -2, -3, and -13, TIMP-1 and -2, and Fas was evaluated by densitometry. Results. At 6 and 12 months of age, OLETF rats showed increased body weight and abnormal 2-hour glucose tolerance tests compared with LETO rats. The apoptosis index of notochordal cells was significantly higher in the OLETF rats than in the LETO rats at both 6 and 12 months of age. The degree of transition of notochordal NP to fibrocartilaginous NP was significantly higher in the OLETF rats than in the LETO rats at 6 and 12 months of age. The expression of MMP-1, -2, -3, and -13, TIMP-1, and Fas was higher in the OLETF rats at 6 and 12 months of age. The expression of TIMP-2 was significantly higher in the OLETF rats than in the LETO rats at 6 months of age, but not at 12. Conclusions. The findings suggest that diabetes is associated with premature, excessive apoptosis of NP notochordal cells. This results in an accelerated transition of a notochordal NP to a fibrocartilaginous NP, which leads to early intervertebral disc degeneration. It remains to be determined if these premature changes are due to hyperglycemia or some other factors associated with diabetes. Understanding the mechanism by which diabetes affects disc degeneration is the first step in designing therapeutic modalities to delay or prevent disc degeneration caused by diabetes mellitus.
KW - Apoptosis
KW - Diabetes
KW - Hyperglycemia
KW - Intervertebral disc degeneration
KW - Notochordal cells
UR - http://www.scopus.com/inward/record.url?scp=73249118652&partnerID=8YFLogxK
U2 - 10.3171/2009.6.SPINE09198
DO - 10.3171/2009.6.SPINE09198
M3 - Article
C2 - 19951028
AN - SCOPUS:73249118652
SN - 1547-5654
VL - 11
SP - 741
EP - 748
JO - Journal of Neurosurgery: Spine
JF - Journal of Neurosurgery: Spine
IS - 6
ER -