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Chondroitin sulfate synthesis promoter

a synthesis promoter and chondroitin technology, applied in the direction of transferases, peptide/protein ingredients, drug compositions, etc., can solve the problems of significant impairment of shock absorption performance and friction reduction performance (lubricating action), and achieve the effect of improving cartilage functions

Inactive Publication Date: 2007-08-30
NAT UNIV CORP TOKYO MEDICAL & DENTAL UNIV +1
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Benefits of technology

[0009]In order to solve the aforementioned object, the present inventors have conducted extensive studies, and have found that among chondroitin sulfate synthesis-related enzymes, chondroitin sulfate glucuronyltransferase (hereinafter sometimes abbreviated as CSGlcAT) and chondroitin sulfate N-acetylgalactosaminyltransferase-1 (hereinafter sometimes referred to as CSGalNAcT-1) are expressed in mouse embryonic cartilage and mouse cartilage differentiated cells in an expression pattern which is considerably correlated with a known aggrecan expression pattern. The inventors have also found that forced over-expression of CSGlcAT and CSGalNAcT-1 in chondroid cells remarkably promotes synthesis of chondroitin sulfate. The inventors have further found that introduction of CSGalNAcT-1 Gene to mouse intervertebral discs increases the levels of chondroitin sulfate in the intervertebral discs, through in vivo experiment.
[0031]The chondroitin sulfate synthesis promoter according to the present invention can promote synthesis of chondroitin sulfate contained in proteoglycan such as aggrecan. Therefore, the synthesis promoter is suitable for improving cartilage functions and treating articular disease and discopathy.

Problems solved by technology

In cartilage of elderly people, shock absorption performance and friction reduction performance (lubricating action) are considerably impaired.

Method used

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Examples

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example 1

Expression of Chondroitin Sulfate Glycosyltransferase in Cartilage

[0112]Humeri were obtained from mouse E16.5 embryos, and in situ hybridization was performed in order to confirm expression of chondroitin sulfate glycosyltransferase in cartilage.

[0113]Digoxigenin (DIG)-11-UTP-labeled single-strand antisense RNA probes corresponding to mouse CSS-1, CSS-2, CSS-3, CSGlcAT, CSGalNAcT-1, CSGalNAcT-2, aggrecan, versican, and type-10 collagen α1 chain (Col10a1) were prepared by use of a DIG RNA labeling kit (product of Boehringer Mannheim) according to the manufacturer's instructions. Each humerus sample was collected from a mouse E16.5 embryo, and a paraffin section thereof was prepared. After removal of paraffin, the section was fixed with 4% paraformaldehyde for 10 minutes and treated with 20-ng / mL protein kinase K (product of Roche) at 37° C. for 7 minutes. Another fixation was performed with 4% paraformaldehyde for 10 minutes, followed by treating with 0.2-mol / L hydrochloric acid for ...

example 2

Expression Patterns of Chondroitin Sulfate Glycosyltransferases During Chondrocyte Differentiation

[0116]Chondrogenic ATDC5 cells were cultured in Dulbecco's modified Eagle medium (DMEM) / F-12 medium containing 5% fetal bovine serum (FBS), penicillin and streptomycin. In order to induce differentiation of chondrocytes, the cells at confluency were treated with 10-μg / mL bovine insulin, 10-μg / mL human transferrin, and 3×10−8-mol / L sodium selenite.

[0117]On days 1, 3, 5, 7, 14, and 21 after induction of differentiation (day 0: at about 80% confluency (growing phase) before induction of differentiation), the expression amount of mRNA (a gene transcription product) corresponding to mouse CSS-1, CSS-2, CSS-3, CSGlcAT, CSGalNAcT-1, CSGalNAcT-2, or aggrecan was determined through real time RT-PCR.

[0118]mRNA was extracted by use of Micro-FastTrack (product of Invitrogen), and cDNA was reverse transcripted therefrom by use of SuperScript First-Strand (product of Invitrogen). The primers and fluo...

example 3

Expression Patterns of Chondroitin Sulfate Glycosyltransferases During Chondrocyte Differentiation

[0121]Chondrogenic N1511 cells were cultured in a minimum essential medium α (α-MEM medium) supplemented with 10% FBS, penicillin, and streptomycin at 37° C. under 5% CO2. The cells at confluency were treated with 1×10−6-mol / L dexamethasone solution and 1×10−7-mol / L rat parathyroid hormone (PTH) solution, to thereby induce differentiation. In a manner similar to that of Example 2, on days 1, 3, 5, 7, 14, and 21 after induction of differentiation (day 0: at about 80% confluency (growing phase) before induction of differentiation), the level of mRNA (a gene transcription product)corresponding to CSS-1, CSS-2, CSS-3, CSGlcAT, CSGalNAcT-1, CSGalNAcT-2, or aggrecan was determined. In a manner similarly to that of Example 2, the aforementioned mRNA levels were standardized by an mRNA level of GAPDH. The thus-standardized mRNA expression levels were plotted as fold numbers with respect to thos...

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Abstract

The invention provides a chondroitin sulfate synthesis promoter useful for the treatment of diseases such as articular disease and discopathy. The chondroitin sulfate synthesis promoter contains, as an active ingredient, chondroitin sulfate glucuronyltransferase protein and / or chondroitin sulfate N-acetylgalactosaminyltransferase-1 protein, or a gene encoding the enzyme protein(s).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to Japanese application number 2006-045813, filed on Feb. 22, 2006 and Japanese application number 2006-224252, filed on Aug. 21, 2006, both of which are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to a chondroitin sulfate synthesis promoter, and to a treatment agent for articular disease and discopathy employing the promoter.[0004]2. Background Art[0005]Cartilage contains a macromolecular substance, called aggrecan, which is predominantly formed of chondroitin sulfate proteoglycan. Aggrecan is a type of proteoglycan in which a polysaccharide sulfate is covalently bound to a core protein, and is known to play an important role in organisms. In cartilage, aggrecan, having a hyaluronic acid-binding domain in a core protein portion, forms a macromolecular complex with a link protein and hyaluronic acid. Aggrecan, having 100 or ...

Claims

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Application Information

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IPC IPC(8): A61K48/00C07H21/04C12N9/10A61K38/48
CPCA61K38/45A61K48/005C07H21/04C12Y204/01226C12Y204/01174C12Y204/01175C12N9/1051A61P19/00A61P19/02
Inventor SAKAI, KENICHIROKIMATA, KOJISHINOMIYA, KENICHIWATANABE, HIDETO
Owner NAT UNIV CORP TOKYO MEDICAL & DENTAL UNIV
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