Histone deacetylase 4 alters cartilage homeostasis in human osteoarthritis

Lü, Jingwei; Sun, Yi-Chih; Ge, Qiting; Teng, Huajian; Jiang, Qing

doi:10.1186/1471-2474-15-438

Cited by 42 publications

(40 citation statements)

References 37 publications

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“…27 The expression of HDAC4 was increased in OA chondrocytes, whereas knockdown of HDAC4 attenuated the induction of catabolic gene expression in chondrocytes. 28 In another study, direct correlation was observed in the enhanced expression of MMP-13 and increased HDAC7 levels in OA cartilage. 29 Treatment with TSA, valproic acid, or MS-275 blocks the cytokine-induced expression of MMP-1 and -13 in human articular chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Makki

Haqqi

2016

The American Journal of Pathology

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Osteoarthritis (OA) is the most common whole-joint disease and is characterized by progressive loss of the cartilage matrix. Matrix metallopeptidase-13 (MMP-13) is a highly active and an abundantly expressed protease in OA cartilage and chondrocytes and degrades type II collagen and proteoglycans. We investigated the mechanism of MMP-13 suppression by histone deacetylase inhibitor vorinostat (SAHA). OA chondrocytes were obtained from knee cartilage after enzymatic digestion and treated with IL-1b in the absence or presence of various histone deacetylase inhibitors. Gene expression was quantified using quantitative RT-PCR. Protein expression and chromatin modifications were determined by Western immunoblotting using specific antibodies. The effect of IL-6 on the expression of MMP-13 was determined by treating chondrocytes with recombinant IL-6 or by IL6 knockdown using IL6-specific siRNA. We found that SAHA is a potent suppressor of IL-1beinduced MMP-13, tumor necrosis factor-a, and other catabolic marker expression in OA chondrocytes. Interestingly, SAHA rescued the COL2A1 and ACAN expression in OA chondrocytes that was down-regulated by IL-1b. Of importance is our finding that IL-6estimulated MMP-13 expression was independent of IL-1b stimulation and was blocked by SAHA, suggesting that SAHA inhibits IL-6 signaling in OA chondrocytes. Taken together, our results suggest that SAHA could be used as a therapeutic agent for the management of OA. (Am J Pathol 2016 http:// dx

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Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Makki

Haqqi

2016

The American Journal of Pathology

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“…In Wnt-5a mRNA silencing, the passage 2 chondrocytes were stimulated for 6 h with IL-1β as previously described (25). The OA-like chondrocytes were divided into three groups: Group I, incubated with complete DMEM for 7 days; group II, incubated with complete DMEM supplemented with empty lentiviral vector for 7 days; group III, incubated with complete DMEM supplemented with LV-Wnt5a-RNAi for 7 days.…”

Section: Methodsmentioning

confidence: 99%

Silencing of Wnt5a prevents interleukin-1β-induced collagen type II degradation in rat chondrocytes

Shi

Man

et al. 2016

Experimental and Therapeutic Medicine

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Osteoarthritis (OA) is a joint disease, and few treatments to date have been able to delay OA progression. The degradation of collagen type II (COL2) in the cartilage matrix is an important initiating factor for OA progression; the upregulation of Wnt5a protein activates COL2 degradation. In the present study, small interfering RNA of Wnt-5a was delivered by a lentiviral vector (LV-Wnt5a-RNAi) to silence Wnt-5a mRNA and prevent COL2 degradation. To determine the function of LV-Wnt5a-RNAi, the OA chondrocyte model (OA-like chondrocytes) were constructed using interleukin (IL)-1β. Detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Wnt-5a mRNA in the OA-like chondrocytes were upregulated in a time-dependent manner, indicating that OA-like chondrocytes were successfully constructed. The bioactivity of OA-like chondrocytes was determined using Live-Dead staining, and the result illustrated that the OA-like chondrocytes stimulated with IL-1β for 6 h remained viable, and these were used in Wnt5a silencing. The OA-like chondrocytes were divided into three groups: Group I, cultivated with common medium; group II, cultivated with common medium supplemented with empty lentiviral vector; group III, cultivated with common medium supplemented with LV-Wnt5a-RNAi. The efficiency of LV-Wnt5a-RNAi transfection was determined using fluorescence microscopy, the result of which indicated that LV-Wnt5a-RNAi could efficiently be transfected into the OA-like chondrocytes. The LV-Wnt5a-RNAi efficiency for the Wnt5a mRNA silencing was determined using RT-qPCR. The result illustrated that the mRNA of Wnt5a in group III was significantly lower in group I compared with that in group II (P<0.05), indicating that the LV-Wnt5a-RNAi could successfully silence Wnt5a mRNA. To further verify whether the silencing of Wnt5a mRNA could prevent COL2 degradation, western blotting and immunohistochemical analyses were performed. The results demonstrated that COL2 in group III was significantly higher compared with that in groups I and II (P<0.05), which illustrated that the silencing of Wnt5a mRNA could prevent COL2 degradation. In conclusion, LV-Wnt5a-RNAi was formed successfully and could efficiently silence Wnt5a mRNA expressed by OA-like chondrocytes. In addition, the silencing of Wnt5a mRNA could prevent the degradation of COL2 in OA-like chondrocytes, confirming that LV-Wnt5a-RNAi may be used as a novel tool for OA treatment.

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“…The abnormal expression of HDAC4 in osteoarthritic cartilage suggests its involvement in promoting the catabolic activity of chondrocytes associated with OA pathogenesis. 6 A significant elevation of HDAC7 in the cartilage of OA patients is reported to contribute to cartilage degradation via promoting MMP-13. 7 These studies suggest that inhibiting certain HDACs may be useful in the management of OA.…”

Section: Role Of Hdacs In Oa Pathogenesismentioning

confidence: 99%

Histone Deacetylase Inhibitory Approaches for the Management of Osteoarthritis

Singh

Nihal

Ahmad

2016

The American Journal of Pathology

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Histone acetylation, a dynamic cellular process, is critical in regulating gene transcription in a variety of ways. This process is tightly regulated by the antagonistic actions of two unique families of enzymes, the histone deacetylases (HDACs) and histone acetyltransferases. HDACs remove acetyl groups (O Z C-CH3) from histones to induce the generation of a compressed, transcriptionally repressed chromatin structure. The HDAC proteins are classified into four groups based on DNA sequence similarity and functional activities.1 Classic HDAC proteins (class I, II, and IV) possess a zinc-dependent active site and are further grouped into 11 subtypes named chronologically HDAC 1 to 11. HDAC class III proteins require the NAD þ cofactor for activity and are known as sirtuins, a family of seven known members (SIRT 1 to 7).The HDAC inhibitors (HDACi) are currently being extensively investigated for the management of a variety of diseases, including inflammatory conditions and cancer. In this issue of The American Journal of Pathology, Makki and Haqqi 2 have found that the drug vorinostat, which is a class I and II HDAC inhibitor, blocks IL-1beinduced expression of matrix metallopeptidase (MMP)-13, tumor necrosis factor-a, and other catabolic factors in human osteoarthritis (OA) chondrocytes obtained from the human knee cartilage.2 Moreover, vorinostat was also found to rescue the collagen type II a and aggrecan proteoglycan expression in OA chondrocytes, which were down-regulated by IL-1b. In addition, the authors have demonstrated that IL6estimulated MMP-13 expression was independent of IL-1b stimulation and was blocked by vorinostat, suggesting that vorinostat inhibits IL-6 signaling in chondrocytes. In this commentary, we discuss the implications of these findings and the potential of HDAC inhibition in the management of OA.

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Histone deacetylase 4 alters cartilage homeostasis in human osteoarthritis

Cited by 42 publications

References 37 publications

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Silencing of Wnt5a prevents interleukin-1β-induced collagen type II degradation in rat chondrocytes

Histone Deacetylase Inhibitory Approaches for the Management of Osteoarthritis

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