Cartilage intermediate layer protein promotes lumbar disc degeneration

Seki, Shoji; Tsumaki, Noriyuki; Motomura, Hiroyuki; Nogami, Makiko; Kawaguchi, Yoshiharu; Hori, Takeshi; Suzuki, Kayo; Yahara, Yasuhito; Higashimoto, Mami; Oya, Takeshi; Ikegawa, Shiro; Kimura, Takeshi

doi:10.1016/j.bbrc.2014.03.025

Cited by 28 publications

(46 citation statements)

References 37 publications

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“…This could bring a direct connection with overexpression of asporin (which plays a role in biomineralization), TGFβip (essential for TGFβ signaling), and the intracellular pool of TGFβ (relationships to collagen calcification) in the M‐side. Moreover Seki et al declared that overexpressed CILP suppressed TFGβ signaling in lumbal disc disease . In our study, CILP2 in the M‐side has a significantly lower concentration, and therefore TGFβ signaling could be disregulated.…”

Section: Discussionmentioning

confidence: 50%

“…Our observations suggest that both of these proteins play specific roles in clubfoot pathology (Figure ). In addition, TGFβ has direct relationships to collagen calcification, and also to another two proteins significantly changed in the presented study—asporin and CILP2 (Figure ) …”

Section: Discussionmentioning

confidence: 61%

“…CILP2 mediates interactions between components of the articular cartilage matrix, and may be associated with collagen VI . Seki et al concluded that CILP suppresses TGFβ signaling and this regulation plays a crucial role in the aetiology of lumbal disc disease . This hypothesis could also fit into the complex aetiology of clubfoot.…”

Section: Discussionmentioning

confidence: 99%

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Novel contribution to clubfoot pathogenesis: The possible role of extracellular matrix proteins

Eckhardt

Novotný

Doubková

et al. 2019

Journal Orthopaedic Research

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Idiopathic pes equinovarus (clubfoot) is a congenital deformity of the feet and lower legs. Clubfoot belongs to a group of fibro‐proliferative disorders but its origin remains unknown. Our study aimed to achieve the first complex proteomic comparison of clubfoot contracted tissue of the foot (medial side; n = 16), with non‐contracted tissue (lateral side; n = 13). We used label‐free mass spectrometry quantification and immunohistochemistry. Seven proteins were observed to be significantly upregulated in the medial side (asporin, collagen type III, V, and VI, versican, tenascin‐C, and transforming growth factor beta induced protein) and four in the lateral side (collagen types XII and XIV, fibromodulin, and cartilage intermediate layer protein 2) of the clubfoot. Comparison of control samples from cadavers brought only two different protein concentrations (collagen types I and VI). We also revealed pathological calcification and intracellular positivity of transforming growth factor beta only in the contracted tissue of clubfoot. Most of the 11 differently expressed proteins are strongly related to the extracellular matrix architecture and we assume that they may play specific roles in the pathogenesis of this deformity. These proteins seem to be promising targets for future investigations and treatment of this disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 61%

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Novel contribution to clubfoot pathogenesis: The possible role of extracellular matrix proteins

Eckhardt

Novotný

Doubková

et al. 2019

Journal Orthopaedic Research

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“…In fact, membrane bound CD109 acts as a co-receptor for TGFβ1 and results in internalization and degradation of TGFβ receptors via binding to Smad73536. Further, CILP inhibits transcriptional activation of matrix genes in NP cells by binding to TGFβ1 and inhibiting the downstream phosphorylation of Smads, thereby promoting disc degeneration37. In addition, small leucine rich proteoglycans (SLRPs) like decorin sequester multiple growth factors including TGFβ1 and directly antagonizes the function of EGFR and IGF-IR38.…”

Section: Discussionmentioning

confidence: 99%

Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus

Matta

Karim

Isenman

et al. 2017

Sci Rep

104

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Degenerative disc disease (DDD) is associated with spinal pain often leading to long-term disability. However, the non-chondrodystrophic canine intervertebral disc is protected from the development of DDD, ostensibly due to its retention of notochordal cells (NC) in the nucleus pulposus (NP). In this study, we hypothesized that secretome analysis of the NC-rich NP will lead to the identification of key proteins that delay the onset of DDD. Using mass-spectrometry, we identified 303 proteins including components of TGFβ- and Wnt-signaling, anti-angiogeneic factors and proteins that inhibit axonal ingrowth in the bioactive fractions of serum free, notochordal cell derived conditioned medium (NCCM). Ingenuity Pathway Analysis revealed TGFβ1 and CTGF as major hubs in protein interaction networks. In vitro treatment with TGFβ1 and CTGF promoted the synthesis of healthy extra-cellular matrix proteins, increased cell proliferation and reduced cell death in human degenerative disc NP cells. A single intra-discal injection of recombinant TGFβ1 and CTGF proteins in a pre-clinical rat-tail disc injury model restored the NC and stem cell rich NP. In conclusion, we demonstrate the potential of TGFβ1 and CTGF to mitigate the progression of disc degeneration and the potential use of these molecules in a molecular therapy to treat the degenerative disc.

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“…CILP1 acts to suppress IGF1-induced proliferation 52 and inhibits transcriptional activation of cartilage genes through TGFB1. 53 Emiliin1 deficiency has been shown to have increased proliferative effects. 12 The combination of proteomic and biomechanical data suggests that excessive proliferation may be the result of loss of CILP1.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease

et al. 2017

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Aortic valve (AV) disease involves stiffening of the AV cusp with progression characterized by inflammation, fibrosis, and calcification. Here, we examine the relationship between biomechanical valve function and proteomic changes before and after the development of AV pathology in the Emilin1−/− mouse model of latent AV disease. Biomechanical studies were performed to quantify tissue stiffness at the macro (micropipette) and micro (atomic force microscopy (AFM)) levels. Micropipette studies showed that the Emilin1−/− AV annulus and cusp regions demonstrated increased stiffness only after the onset of AV disease. AFM studies showed that the Emilin1−/− cusp stiffens before the onset of AV disease and worsens with the onset of disease. Proteomes from AV cusps were investigated to identify protein functions, pathways, and interaction network alterations that occur with age- and genotype-related valve stiffening. Protein alterations due to Emilin1 deficiency, including changes in pathways and functions, preceded biomechanical aberrations, resulting in marked depletion of extracellular matrix (ECM) proteins interacting with TGFB1, including latent transforming growth factor beta 3 (LTBP3), fibulin 5 (FBLN5), and cartilage intermediate layer protein 1 (CILP1). This study identifies proteomic dysregulation is associated with biomechanical dysfunction as early pathogenic processes in the Emilin1−/− model of AV disease.

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Cartilage intermediate layer protein promotes lumbar disc degeneration

Cited by 28 publications

References 37 publications

Novel contribution to clubfoot pathogenesis: The possible role of extracellular matrix proteins

Novel contribution to clubfoot pathogenesis: The possible role of extracellular matrix proteins

Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus

Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease

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