title: Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis.
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. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1058-1066, 2017.
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China.
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Healthcare, Jiangxi Maternal and Child Health Hospital, Nanchang, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China.
authors.forename: Zhaoxun
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China.
authors.forename: Zhongzu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Hikata
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Iwanami
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China.|Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Cao
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose; D006801:Humans; D006984:Hypertrophy; D017843:Ligamentum Flavum / Q000378:metabolism* / Q000473:pathology; D008159:Lumbar Vertebrae / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D012236:Rhodanine / Q000031:analogs & derivatives; D013012:Sorbitol / Q000378:metabolism*; D013130:Spinal Stenosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D053778:Thiazolidines; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D005947:Glucose; D012236:Rhodanine; D013012:Sorbitol; D053778:Thiazolidines; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C038131:epalrestat
keywords: diabetes mellitus; ligamentumflavum; lumbar spinal canal stenosis; sorbitol