Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis

Jiaquan Luo, Lu Huang, Zhuo Chen, Zhaoxun Zeng, Takeshi Miyamoto, Hao Wu, Zhongzu Zhang, Zhimin Pan, Nobuyuki Fujita, Tomohiro Hikata, Akio Iwanami, Takashi Tsuji, Ken Ishii, Masaya Nakamura, Morio Matsumoto, Kota Watanabe, Kai Cao

Research output: Contribution to journalArticle

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Abstract

The pathomechanism of the ligamentum flavum (LF) hypertrophy in diabetic patients with lumbar spinal canal stenosis (LSCS) remains unclear. A cross-sectional study was undertaken to investigate the mechanism of LF hypertrophy in these patients. Twenty-four diabetic and 20 normoglycemic patients with LSCS were enrolled in the study. The structure of the LF in the study subjects was evaluated using histological and immunohistochemical methods, and the levels of sorbitol, pro-inflammatory cytokines, and the fibrogenic factor, TGF-β1, in the LF were analyzed. In vitro experiments were performed using NIH3T3 fibroblasts to evaluate the effect of high-glucose conditions and an aldose reductase inhibitor on the cellular production of sorbitol, pro-inflammatory factors, and TGF-β1. We found that the LF of diabetic patients exhibited significantly higher levels of sorbitol and pro-inflammatory cytokines, TGF-β1 and of CD68-positive staining than that of the normoglycemic subjects. The diabetic LF was significantly thicker than that of the controls, and showed evidence of degeneration. The high glucose-cultured fibroblasts exhibited significantly higher levels of sorbitol, pro-inflammatory factors, and TGF-β1 compared to the low glucose-cultured cells, and these levels were dose-dependently reduced by treatment with the aldose reductase inhibitor. Taken together, our data suggests that increased sorbitol levels in the LF of diabetic patients results in increased production of pro-inflammatory and fibrogenic factor, which contribute to LF hypertrophy, and could increase the susceptibility of diabetic patients to LSCS. Furthermore, aldose reductase inhibition effectively reduced the levels of sorbitol and sorbitol-induced pro-inflammatory factor expression in high glucose-cultured fibroblasts.

Original languageEnglish
Pages (from-to)1058-1066
Number of pages9
JournalJournal of Orthopaedic Research
Volume35
Issue number5
DOIs
Publication statusPublished - 01-05-2017
Externally publishedYes

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Ligamentum Flavum
Spinal Stenosis
Spinal Canal
Sorbitol
Aldehyde Reductase
Hypertrophy
Glucose
Fibroblasts
Cytokines
Cultured Cells
Cross-Sectional Studies
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Orthopedics and Sports Medicine

Cite this

Luo, Jiaquan ; Huang, Lu ; Chen, Zhuo ; Zeng, Zhaoxun ; Miyamoto, Takeshi ; Wu, Hao ; Zhang, Zhongzu ; Pan, Zhimin ; Fujita, Nobuyuki ; Hikata, Tomohiro ; Iwanami, Akio ; Tsuji, Takashi ; Ishii, Ken ; Nakamura, Masaya ; Matsumoto, Morio ; Watanabe, Kota ; Cao, Kai. / Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis. In: Journal of Orthopaedic Research. 2017 ; Vol. 35, No. 5. pp. 1058-1066.
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abstract = "The pathomechanism of the ligamentum flavum (LF) hypertrophy in diabetic patients with lumbar spinal canal stenosis (LSCS) remains unclear. A cross-sectional study was undertaken to investigate the mechanism of LF hypertrophy in these patients. Twenty-four diabetic and 20 normoglycemic patients with LSCS were enrolled in the study. The structure of the LF in the study subjects was evaluated using histological and immunohistochemical methods, and the levels of sorbitol, pro-inflammatory cytokines, and the fibrogenic factor, TGF-β1, in the LF were analyzed. In vitro experiments were performed using NIH3T3 fibroblasts to evaluate the effect of high-glucose conditions and an aldose reductase inhibitor on the cellular production of sorbitol, pro-inflammatory factors, and TGF-β1. We found that the LF of diabetic patients exhibited significantly higher levels of sorbitol and pro-inflammatory cytokines, TGF-β1 and of CD68-positive staining than that of the normoglycemic subjects. The diabetic LF was significantly thicker than that of the controls, and showed evidence of degeneration. The high glucose-cultured fibroblasts exhibited significantly higher levels of sorbitol, pro-inflammatory factors, and TGF-β1 compared to the low glucose-cultured cells, and these levels were dose-dependently reduced by treatment with the aldose reductase inhibitor. Taken together, our data suggests that increased sorbitol levels in the LF of diabetic patients results in increased production of pro-inflammatory and fibrogenic factor, which contribute to LF hypertrophy, and could increase the susceptibility of diabetic patients to LSCS. Furthermore, aldose reductase inhibition effectively reduced the levels of sorbitol and sorbitol-induced pro-inflammatory factor expression in high glucose-cultured fibroblasts.",
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Luo, J, Huang, L, Chen, Z, Zeng, Z, Miyamoto, T, Wu, H, Zhang, Z, Pan, Z, Fujita, N, Hikata, T, Iwanami, A, Tsuji, T, Ishii, K, Nakamura, M, Matsumoto, M, Watanabe, K & Cao, K 2017, 'Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis', Journal of Orthopaedic Research, vol. 35, no. 5, pp. 1058-1066. https://doi.org/10.1002/jor.23302

Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis. / Luo, Jiaquan; Huang, Lu; Chen, Zhuo; Zeng, Zhaoxun; Miyamoto, Takeshi; Wu, Hao; Zhang, Zhongzu; Pan, Zhimin; Fujita, Nobuyuki; Hikata, Tomohiro; Iwanami, Akio; Tsuji, Takashi; Ishii, Ken; Nakamura, Masaya; Matsumoto, Morio; Watanabe, Kota; Cao, Kai.

In: Journal of Orthopaedic Research, Vol. 35, No. 5, 01.05.2017, p. 1058-1066.

Research output: Contribution to journalArticle

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T1 - Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis

AU - Luo, Jiaquan

AU - Huang, Lu

AU - Chen, Zhuo

AU - Zeng, Zhaoxun

AU - Miyamoto, Takeshi

AU - Wu, Hao

AU - Zhang, Zhongzu

AU - Pan, Zhimin

AU - Fujita, Nobuyuki

AU - Hikata, Tomohiro

AU - Iwanami, Akio

AU - Tsuji, Takashi

AU - Ishii, Ken

AU - Nakamura, Masaya

AU - Matsumoto, Morio

AU - Watanabe, Kota

AU - Cao, Kai

PY - 2017/5/1

Y1 - 2017/5/1

N2 - The pathomechanism of the ligamentum flavum (LF) hypertrophy in diabetic patients with lumbar spinal canal stenosis (LSCS) remains unclear. A cross-sectional study was undertaken to investigate the mechanism of LF hypertrophy in these patients. Twenty-four diabetic and 20 normoglycemic patients with LSCS were enrolled in the study. The structure of the LF in the study subjects was evaluated using histological and immunohistochemical methods, and the levels of sorbitol, pro-inflammatory cytokines, and the fibrogenic factor, TGF-β1, in the LF were analyzed. In vitro experiments were performed using NIH3T3 fibroblasts to evaluate the effect of high-glucose conditions and an aldose reductase inhibitor on the cellular production of sorbitol, pro-inflammatory factors, and TGF-β1. We found that the LF of diabetic patients exhibited significantly higher levels of sorbitol and pro-inflammatory cytokines, TGF-β1 and of CD68-positive staining than that of the normoglycemic subjects. The diabetic LF was significantly thicker than that of the controls, and showed evidence of degeneration. The high glucose-cultured fibroblasts exhibited significantly higher levels of sorbitol, pro-inflammatory factors, and TGF-β1 compared to the low glucose-cultured cells, and these levels were dose-dependently reduced by treatment with the aldose reductase inhibitor. Taken together, our data suggests that increased sorbitol levels in the LF of diabetic patients results in increased production of pro-inflammatory and fibrogenic factor, which contribute to LF hypertrophy, and could increase the susceptibility of diabetic patients to LSCS. Furthermore, aldose reductase inhibition effectively reduced the levels of sorbitol and sorbitol-induced pro-inflammatory factor expression in high glucose-cultured fibroblasts.

AB - The pathomechanism of the ligamentum flavum (LF) hypertrophy in diabetic patients with lumbar spinal canal stenosis (LSCS) remains unclear. A cross-sectional study was undertaken to investigate the mechanism of LF hypertrophy in these patients. Twenty-four diabetic and 20 normoglycemic patients with LSCS were enrolled in the study. The structure of the LF in the study subjects was evaluated using histological and immunohistochemical methods, and the levels of sorbitol, pro-inflammatory cytokines, and the fibrogenic factor, TGF-β1, in the LF were analyzed. In vitro experiments were performed using NIH3T3 fibroblasts to evaluate the effect of high-glucose conditions and an aldose reductase inhibitor on the cellular production of sorbitol, pro-inflammatory factors, and TGF-β1. We found that the LF of diabetic patients exhibited significantly higher levels of sorbitol and pro-inflammatory cytokines, TGF-β1 and of CD68-positive staining than that of the normoglycemic subjects. The diabetic LF was significantly thicker than that of the controls, and showed evidence of degeneration. The high glucose-cultured fibroblasts exhibited significantly higher levels of sorbitol, pro-inflammatory factors, and TGF-β1 compared to the low glucose-cultured cells, and these levels were dose-dependently reduced by treatment with the aldose reductase inhibitor. Taken together, our data suggests that increased sorbitol levels in the LF of diabetic patients results in increased production of pro-inflammatory and fibrogenic factor, which contribute to LF hypertrophy, and could increase the susceptibility of diabetic patients to LSCS. Furthermore, aldose reductase inhibition effectively reduced the levels of sorbitol and sorbitol-induced pro-inflammatory factor expression in high glucose-cultured fibroblasts.

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