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Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: a novel mechanism of human osteoarthritis cartilage degeneration.

Cao K, Wei L, Zhang Z, Guo L, Zhang C, Li Y, Sun C, Sun X, Wang S, Li P, Wei X - Arthritis Res. Ther. (2014)

Bottom Line: The levels of HDAC4 in the cartilage from OA patients and healthy 40- to 60-year-old donors were decreased to 31% and 65% compared with specimens from 20- to 40-year-old healthy donors, respectively (P <0.05).In addition, the data also shows that overexpression of HDAC4 not only decreased the expression of interleukin (IL)-1β, Cox2 and iNos and increased the expression of aggrecan, but also partially blocked the effect of IL-1β on expression of catabolic events in human OA chondrocytes.In contrast, inhibition of HDAC4 by TSA drug had an opposite effect.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: To investigate if decreased histone deacetylase 4 (HDAC4) is associated with human osteoarthritis (OA) cartilage degeneration by releasing HDAC4 inhibition of runt-related transcription factor-2 (Runx2) resulting in increase of OA cartilage degeneration-related genes.

Methods: The mRNA and protein levels of HDAC4, Runx2, matrix metalloproteinase (MMP)-13, Indian hedgehog (Ihh) and type X collagen were detected by performing real-time PCR (RT-PCR), western blotting and immunohistochemistry on specimens from human OA and normal cartilage. To further explore the mechanism of regulation of Runx2 and OA-related genes by HDAC4, changes in these OA-related genes were further quantified by RT-PCR after overexpression of HDAC4 and knockdown of HDAC4 by siRNA. Runx2 and MMP-13 promoter activities were measured by dual luciferase assays.

Results: The levels of HDAC4 in the cartilage from OA patients and healthy 40- to 60-year-old donors were decreased to 31% and 65% compared with specimens from 20- to 40-year-old healthy donors, respectively (P <0.05). Decreased HDAC4 was associated with increased Runx2 and other OA-related genes in human OA cartilage, specifically: MMP-13, Ihh and type X collagen. Exogenous HDAC4 decreased the mRNA levels of Runx2, MMP1, MMP3, MMP-13, type X collagen, Ihh, ADAMTS-4 and -5, and increased the mRNA of type II collagen. In addition, the data also shows that overexpression of HDAC4 not only decreased the expression of interleukin (IL)-1β, Cox2 and iNos and increased the expression of aggrecan, but also partially blocked the effect of IL-1β on expression of catabolic events in human OA chondrocytes. HDAC4 also inhibited Runx2 promoter activity and MMP13 promotor activity in a dose-dependent manner. In contrast, inhibition of HDAC4 by TSA drug had an opposite effect.

Conclusions: Our study is the first to demonstrate that decreased HDAC4 contributes, at least in part, to the pathogenesis of OA cartilage degeneration. Thus, HDAC4 may have chondroprotective properties by inhibiting Runx2 and OA-related genes.

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Increased MMP-13, Ihh and type X collagen expression in OA cartilage. (A) Immunohistochemistry was performed to detect MMP-13, Ihh and type X collagen. The boxed regions indicate the magnified area shown at the right side. (B) Real-time PCR indicates that the level of MMP-13, Ihh and type X collagen increased in OA cartilages (n = 3) compared with normal cartilage (n = 3) (*P <0.05). (C, D) Western blotting showed expression of MMP-13, Ihh and type X collagen increased in OA samples compared with normal controls. Semi-quality by densitometry showed the mean concentration of MMP-13, Ihh and type X collagen in the cartilage of OA patients (n = 3) compared with the cartilage of normal controls (40- to 60-year-olds) (n = 3) (*P <0.05). MMP, matrix metalloprotease; OA, osteoarthritis; SD, standard deviation.
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Fig3: Increased MMP-13, Ihh and type X collagen expression in OA cartilage. (A) Immunohistochemistry was performed to detect MMP-13, Ihh and type X collagen. The boxed regions indicate the magnified area shown at the right side. (B) Real-time PCR indicates that the level of MMP-13, Ihh and type X collagen increased in OA cartilages (n = 3) compared with normal cartilage (n = 3) (*P <0.05). (C, D) Western blotting showed expression of MMP-13, Ihh and type X collagen increased in OA samples compared with normal controls. Semi-quality by densitometry showed the mean concentration of MMP-13, Ihh and type X collagen in the cartilage of OA patients (n = 3) compared with the cartilage of normal controls (40- to 60-year-olds) (n = 3) (*P <0.05). MMP, matrix metalloprotease; OA, osteoarthritis; SD, standard deviation.

Mentions: Strong staining for MMP-13, Ihh and type X collagen was observed in OA cartilage compared with normal cartilage (Figure 3A). Real-time PCR results indicated that the level of MMP-13, Ihh and type X collagen increased 5.24-, 2.98- and 3.65-fold, respectively, in OA cartilages compared with normal cartilage (P <0.05) (Figure 3B). Similar findings were made by western blotting. (Figure 3C). Semi-quantification of western blots showed that the concentration of MMP-13, Ihh and type X collagen was increased 278%, 257% and 251% in cartilage from OA patients compared with those from normal controls, respectively (P <0.05) (Figure 3C,D).Figure 3


Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: a novel mechanism of human osteoarthritis cartilage degeneration.

Cao K, Wei L, Zhang Z, Guo L, Zhang C, Li Y, Sun C, Sun X, Wang S, Li P, Wei X - Arthritis Res. Ther. (2014)

Increased MMP-13, Ihh and type X collagen expression in OA cartilage. (A) Immunohistochemistry was performed to detect MMP-13, Ihh and type X collagen. The boxed regions indicate the magnified area shown at the right side. (B) Real-time PCR indicates that the level of MMP-13, Ihh and type X collagen increased in OA cartilages (n = 3) compared with normal cartilage (n = 3) (*P <0.05). (C, D) Western blotting showed expression of MMP-13, Ihh and type X collagen increased in OA samples compared with normal controls. Semi-quality by densitometry showed the mean concentration of MMP-13, Ihh and type X collagen in the cartilage of OA patients (n = 3) compared with the cartilage of normal controls (40- to 60-year-olds) (n = 3) (*P <0.05). MMP, matrix metalloprotease; OA, osteoarthritis; SD, standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4265470&req=5

Fig3: Increased MMP-13, Ihh and type X collagen expression in OA cartilage. (A) Immunohistochemistry was performed to detect MMP-13, Ihh and type X collagen. The boxed regions indicate the magnified area shown at the right side. (B) Real-time PCR indicates that the level of MMP-13, Ihh and type X collagen increased in OA cartilages (n = 3) compared with normal cartilage (n = 3) (*P <0.05). (C, D) Western blotting showed expression of MMP-13, Ihh and type X collagen increased in OA samples compared with normal controls. Semi-quality by densitometry showed the mean concentration of MMP-13, Ihh and type X collagen in the cartilage of OA patients (n = 3) compared with the cartilage of normal controls (40- to 60-year-olds) (n = 3) (*P <0.05). MMP, matrix metalloprotease; OA, osteoarthritis; SD, standard deviation.
Mentions: Strong staining for MMP-13, Ihh and type X collagen was observed in OA cartilage compared with normal cartilage (Figure 3A). Real-time PCR results indicated that the level of MMP-13, Ihh and type X collagen increased 5.24-, 2.98- and 3.65-fold, respectively, in OA cartilages compared with normal cartilage (P <0.05) (Figure 3B). Similar findings were made by western blotting. (Figure 3C). Semi-quantification of western blots showed that the concentration of MMP-13, Ihh and type X collagen was increased 278%, 257% and 251% in cartilage from OA patients compared with those from normal controls, respectively (P <0.05) (Figure 3C,D).Figure 3

Bottom Line: The levels of HDAC4 in the cartilage from OA patients and healthy 40- to 60-year-old donors were decreased to 31% and 65% compared with specimens from 20- to 40-year-old healthy donors, respectively (P <0.05).In addition, the data also shows that overexpression of HDAC4 not only decreased the expression of interleukin (IL)-1β, Cox2 and iNos and increased the expression of aggrecan, but also partially blocked the effect of IL-1β on expression of catabolic events in human OA chondrocytes.In contrast, inhibition of HDAC4 by TSA drug had an opposite effect.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: To investigate if decreased histone deacetylase 4 (HDAC4) is associated with human osteoarthritis (OA) cartilage degeneration by releasing HDAC4 inhibition of runt-related transcription factor-2 (Runx2) resulting in increase of OA cartilage degeneration-related genes.

Methods: The mRNA and protein levels of HDAC4, Runx2, matrix metalloproteinase (MMP)-13, Indian hedgehog (Ihh) and type X collagen were detected by performing real-time PCR (RT-PCR), western blotting and immunohistochemistry on specimens from human OA and normal cartilage. To further explore the mechanism of regulation of Runx2 and OA-related genes by HDAC4, changes in these OA-related genes were further quantified by RT-PCR after overexpression of HDAC4 and knockdown of HDAC4 by siRNA. Runx2 and MMP-13 promoter activities were measured by dual luciferase assays.

Results: The levels of HDAC4 in the cartilage from OA patients and healthy 40- to 60-year-old donors were decreased to 31% and 65% compared with specimens from 20- to 40-year-old healthy donors, respectively (P <0.05). Decreased HDAC4 was associated with increased Runx2 and other OA-related genes in human OA cartilage, specifically: MMP-13, Ihh and type X collagen. Exogenous HDAC4 decreased the mRNA levels of Runx2, MMP1, MMP3, MMP-13, type X collagen, Ihh, ADAMTS-4 and -5, and increased the mRNA of type II collagen. In addition, the data also shows that overexpression of HDAC4 not only decreased the expression of interleukin (IL)-1β, Cox2 and iNos and increased the expression of aggrecan, but also partially blocked the effect of IL-1β on expression of catabolic events in human OA chondrocytes. HDAC4 also inhibited Runx2 promoter activity and MMP13 promotor activity in a dose-dependent manner. In contrast, inhibition of HDAC4 by TSA drug had an opposite effect.

Conclusions: Our study is the first to demonstrate that decreased HDAC4 contributes, at least in part, to the pathogenesis of OA cartilage degeneration. Thus, HDAC4 may have chondroprotective properties by inhibiting Runx2 and OA-related genes.

Show MeSH
Related in: MedlinePlus