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Xylosyltransferase-I regulates glycosaminoglycan synthesis during the pathogenic process of human osteoarthritis.

Venkatesan N, Barré L, Bourhim M, Magdalou J, Mainard D, Netter P, Fournel-Gigleux S, Ouzzine M - PLoS ONE (2012)

Bottom Line: The results showed that GAG synthesis and content increased in cartilage from areas flanking OA lesions compared to cartilage from macroscopically "normal" unaffected regions, while decreased in "late-stage" OA cartilage lesions.This increase in anabolic state was associated with a marked upregulation of XT-I expression and activity in cartilage "next to lesion" while a decrease in the "late-stage" OA cartilage.Theses observations may account for upregulation of XT-I and sustained GAG synthesis prior to the development of cartilage lesions during the pathogenic process of OA.

View Article: PubMed Central - PubMed

Affiliation: UMR 7561 CNRS-Université Nancy 1, Faculté de Médecine, Vandœuvre-lès-Nancy, France.

ABSTRACT
Loss of glycosaminoglycan (GAG) chains of proteoglycans (PGs) is an early event of osteoarthritis (OA) resulting in cartilage degradation that has been previously demonstrated in both huma and experimental OA models. However, the mechanism of GAG loss and the role of xylosyltransferase-I (XT-I) that initiates GAG biosynthesis onto PG molecules in the pathogenic process of human OA are unknown. In this study, we have characterized XT-I expression and activity together with GAG synthesis in human OA cartilage obtained from different regions of the same joint, defined as "normal", "late-stage" or adjacent to "late-stage". The results showed that GAG synthesis and content increased in cartilage from areas flanking OA lesions compared to cartilage from macroscopically "normal" unaffected regions, while decreased in "late-stage" OA cartilage lesions. This increase in anabolic state was associated with a marked upregulation of XT-I expression and activity in cartilage "next to lesion" while a decrease in the "late-stage" OA cartilage. Importantly, XT-I inhibition by shRNA or forced-expression with a pCMV-XT-I construct correlated with the modulation of GAG anabolism in human cartilage explants. The observation that XT-I gene expression was down-regulated by IL-1β and up-regulated by TGF-β1 indicates that these cytokines may play a role in regulating GAG content in human OA. Noteworthy, expression of IL-1β receptor (IL-1R1) was down-regulated whereas that of TGF-β1 was up-regulated in early OA cartilage. Theses observations may account for upregulation of XT-I and sustained GAG synthesis prior to the development of cartilage lesions during the pathogenic process of OA.

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Effect of IL-1β (A) and TGF-β1 (B) on XT-I gene expression in normal articular cartilage.Cartilage samples isolated from normal regions of human femoral condyle was exposed to IL-1β or TGF-β1 and then XT-I gene expression was analyzed by qPCR. Measurements were normalized to control (non treated). Each value represents the mean ± SD of 3 experiments per parameter per joint per patient. *Significantly (P<0.05) lower than control group; #significantly (P<0.01) higher than control group.
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pone-0034020-g008: Effect of IL-1β (A) and TGF-β1 (B) on XT-I gene expression in normal articular cartilage.Cartilage samples isolated from normal regions of human femoral condyle was exposed to IL-1β or TGF-β1 and then XT-I gene expression was analyzed by qPCR. Measurements were normalized to control (non treated). Each value represents the mean ± SD of 3 experiments per parameter per joint per patient. *Significantly (P<0.05) lower than control group; #significantly (P<0.01) higher than control group.

Mentions: Beside its ability to induce degradation of articular cartilage, the proinflammatory cytokine IL-1β has been shown to suppress the synthesis of PGs by chondrocytes [28], [29]. In contrast the growth factor TGF-β1 is a potent inducer of chondrocyte matrix deposition [30]–[32]. We investigated whether XT-I gene expression is regulated by IL-1β and TGF-β1. Cartilage explants were treated or not with IL-1β and TGF-β1, respectively and XT-I expression was analyzed using quantitative PCR. Our result showed that IL-1β down-regulated the expression of XT-I by about 50% (Fig. 8A). In contrast, TGF-β1 induced the expression by about 3-fold (Fig. 8B). These results clearly indicated that XT-I gene expression is regulated by the two main cytokines involved in cartilage metabolism.


Xylosyltransferase-I regulates glycosaminoglycan synthesis during the pathogenic process of human osteoarthritis.

Venkatesan N, Barré L, Bourhim M, Magdalou J, Mainard D, Netter P, Fournel-Gigleux S, Ouzzine M - PLoS ONE (2012)

Effect of IL-1β (A) and TGF-β1 (B) on XT-I gene expression in normal articular cartilage.Cartilage samples isolated from normal regions of human femoral condyle was exposed to IL-1β or TGF-β1 and then XT-I gene expression was analyzed by qPCR. Measurements were normalized to control (non treated). Each value represents the mean ± SD of 3 experiments per parameter per joint per patient. *Significantly (P<0.05) lower than control group; #significantly (P<0.01) higher than control group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316535&req=5

pone-0034020-g008: Effect of IL-1β (A) and TGF-β1 (B) on XT-I gene expression in normal articular cartilage.Cartilage samples isolated from normal regions of human femoral condyle was exposed to IL-1β or TGF-β1 and then XT-I gene expression was analyzed by qPCR. Measurements were normalized to control (non treated). Each value represents the mean ± SD of 3 experiments per parameter per joint per patient. *Significantly (P<0.05) lower than control group; #significantly (P<0.01) higher than control group.
Mentions: Beside its ability to induce degradation of articular cartilage, the proinflammatory cytokine IL-1β has been shown to suppress the synthesis of PGs by chondrocytes [28], [29]. In contrast the growth factor TGF-β1 is a potent inducer of chondrocyte matrix deposition [30]–[32]. We investigated whether XT-I gene expression is regulated by IL-1β and TGF-β1. Cartilage explants were treated or not with IL-1β and TGF-β1, respectively and XT-I expression was analyzed using quantitative PCR. Our result showed that IL-1β down-regulated the expression of XT-I by about 50% (Fig. 8A). In contrast, TGF-β1 induced the expression by about 3-fold (Fig. 8B). These results clearly indicated that XT-I gene expression is regulated by the two main cytokines involved in cartilage metabolism.

Bottom Line: The results showed that GAG synthesis and content increased in cartilage from areas flanking OA lesions compared to cartilage from macroscopically "normal" unaffected regions, while decreased in "late-stage" OA cartilage lesions.This increase in anabolic state was associated with a marked upregulation of XT-I expression and activity in cartilage "next to lesion" while a decrease in the "late-stage" OA cartilage.Theses observations may account for upregulation of XT-I and sustained GAG synthesis prior to the development of cartilage lesions during the pathogenic process of OA.

View Article: PubMed Central - PubMed

Affiliation: UMR 7561 CNRS-Université Nancy 1, Faculté de Médecine, Vandœuvre-lès-Nancy, France.

ABSTRACT
Loss of glycosaminoglycan (GAG) chains of proteoglycans (PGs) is an early event of osteoarthritis (OA) resulting in cartilage degradation that has been previously demonstrated in both huma and experimental OA models. However, the mechanism of GAG loss and the role of xylosyltransferase-I (XT-I) that initiates GAG biosynthesis onto PG molecules in the pathogenic process of human OA are unknown. In this study, we have characterized XT-I expression and activity together with GAG synthesis in human OA cartilage obtained from different regions of the same joint, defined as "normal", "late-stage" or adjacent to "late-stage". The results showed that GAG synthesis and content increased in cartilage from areas flanking OA lesions compared to cartilage from macroscopically "normal" unaffected regions, while decreased in "late-stage" OA cartilage lesions. This increase in anabolic state was associated with a marked upregulation of XT-I expression and activity in cartilage "next to lesion" while a decrease in the "late-stage" OA cartilage. Importantly, XT-I inhibition by shRNA or forced-expression with a pCMV-XT-I construct correlated with the modulation of GAG anabolism in human cartilage explants. The observation that XT-I gene expression was down-regulated by IL-1β and up-regulated by TGF-β1 indicates that these cytokines may play a role in regulating GAG content in human OA. Noteworthy, expression of IL-1β receptor (IL-1R1) was down-regulated whereas that of TGF-β1 was up-regulated in early OA cartilage. Theses observations may account for upregulation of XT-I and sustained GAG synthesis prior to the development of cartilage lesions during the pathogenic process of OA.

Show MeSH
Related in: MedlinePlus