title: Cartilage intermediate layer protein promotes lumbar disc degeneration.
abstract: Lumbar disc disease (LDD) is one of the most common musculoskeletal disorders, and accompanies intervertebral disc degeneration. CILP encodes cartilage intermediate layer protein, which is highly associated with LDD. Moreover, CILP inhibits transcriptional activation of cartilage matrix genes in nucleus pulposus (NP) cells in vitro by binding to TGF-β1 and inhibiting the phosphorylation of Smads. However, the aetiology and mechanism of pathogenesis of LDD in vivo are unknown. To demonstrate the role of CILP in LDD in vivo, we generated transgenic mice that express CILP specifically in the intervertebral disc tissues and assessed whether CILP exacerbates disc degeneration. Degeneration of the intervertebral discs was assessed using magnetic resonance imaging (MRI) and histology. The level of phosphorylation of Smad2/3 in intervertebral discs was measured to determine whether overexpressed CILP suppressed TGF-beta signalling. Although the macroscopic skeletal phenotype of transgenic mice appeared normal, histological findings revealed significant degeneration of lumbar discs. MRI analysis of the lumbar intervertebral discs indicated a significantly lower signal intensity of the nucleus pulposus where CILP was overexpressed. Intervertebral disc degeneration was also observed. The number of phosphorylation of Smad2/3 immuno-positive cells in the NP significantly was decreased in CILP transgenic mice compared with normal mice. In summary, overexpression of CILP in the NP promotes disc degeneration, indicating that CILP plays a direct role in the pathogenesis of LDD.
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan. Electronic address: seki@med.u-toyama.ac.jp.
authors.forename: Shoji
authors.initials: S
authors.lastname: Seki
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Tsumaki
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Motomura
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Nogami
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hori
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Yahara
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Higashimoto
authors.affiliation: Department of Pathology, Niigata Prefectural Central Hospital, 205 Shinminamimachi, Joetsu, Niigata 943-0192, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Oya
authors.affiliation: Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000818:Animals; D006801:Humans; D007403:Intervertebral Disc / Q000378:metabolism / Q000473:pathology*; D055959:Intervertebral Disc Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007405:Intervertebral Disc Displacement / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008159:Lumbar Vertebrae / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D011755:Pyrophosphatases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; C000589044:CILP protein, mouse; D011755:Pyrophosphatases
keywords: Cartilage intermediate layer protein; Lumbar disc degeneration; Tissue specific promoter; Transforming growth factor-beta; Transgenic mice