Positive Effects of a Young Systemic Environment and High Growth Differentiation Factor 11 Levels on Chondrocyte Proliferation and Cartilage Matrix Synthesis in Old Mice

Li, Lü; Wei, Xiaochun; Wang, Dongming; Lv, Zhi; Geng, Xiang; Li, Pengcui; Lu, Jiangong; Wang, Kaihang; Wang, Xiaohu; Sun, Jian; Cao, Xiaoming; Wei, Lei

doi:10.1002/art.41230

Cited by 25 publications

(15 citation statements)

References 40 publications

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“…Furthermore, spontaneous OA in some mice was only classified as moderate by the time of 15-month old. 16 These results suggest that HDAC4 deletion could early induce age-related spontaneous OA. SafO staining showed cartilage surface defects in AggH-Tam group mice classified as early-stage OA while no obvious changes were observed in the other two control groups ( Figure 3D and E ).…”

Section: Discussionmentioning

confidence: 82%

“…Due to the dwarfism and early death of HDAC4-ablation mice at birth and long period of age-related research, 5 2-month-old (as young adult mice) was chosen as the injection time for age-related OA induction to avoid the possible skeleton development influence of gene knockout. 15 , 16 …”

Section: Methodsmentioning

confidence: 99%

“…Non template control was added each time in all the assays. 18S rRNA (for mice 16 ) and GAPDH (for rats 21 ) was used to normalize the gene expression levels. The primers were designed using Primer-BLAST (NCBI primer designing tool).…”

Section: Methodsmentioning

confidence: 99%

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The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy

Dong¹,

Ma²,

Yang³

et al. 2022

JIR

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Purpose To determine the role of histone deacetylase 4 (HDAC4)-controlled chondrocyte hypertrophy in the onset and development of age-related osteoarthritis (OA). Methods Morphological analysis of human knee cartilages was performed to observe structural changes during cartilage degeneration. HDAC4 expression was deleted in adult aggrecan (Acan)-CreERT2; HDAC4fl/fl transgenic mice. The onset and development of age-related OA were investigated in transgenic and control mice using hematoxylin and eosin (H&E) and Safranin O staining. Furthermore, the progression of ACLT-induced OA following adenovirus-mediated HDAC4 overexpression was explored in rats. The expression levels of genes related to hypertrophy, cartilage matrix and its digestion, and chondrocyte proliferation were investigated using qPCR. Immunohistochemistry (IHC) was used to explore the mechanisms underlying HDAC4-controlled age-related changes in OA progression. Results In human cartilage, we performed morphological analysis and IHC, the results showed that hypertrophy-related structural changes are related to HDAC4 expression. Age-related OA was detected early (OARSI scores 2.7 at 8-month-old) following HDAC4 deletion in 2-month-old mice. Furthermore, qPCR and IHC results showed changes in hypertrophy-related genes Col10a1, Runx2 and Sox9 in chondrocytes, particularly in the expression of Runt-related transcription factor 2 (Runx2, 13.29±0.99 fold). The expression of the main cartilage matrix-related genes Col2a1 and Acan decreased, that of cartilage matrix digestion-related gene MMP-13 increased, while that of chondrocyte proliferation-related genes PTHrP, Ihh and Gli1 changed. In contrast, rat cartilage’s qPCR and IHC results showed opposite outcomes after HDAC4 overexpression. Conclusion Based on the results above, we concluded that HDAC4 expression regulates the onset and development of age-related OA by controlling chondrocyte hypertrophy. These results may help in the development of early diagnosis and treatment of age-related OA.

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Section: Discussionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

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The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy

Dong¹,

Ma²,

Yang³

et al. 2022

JIR

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“…Lin28a, an RNA-binding protein that is highly expressed in embryonic stem cells, helps generate energy for cellular functions through glycolytic metabolism, and a decrease in its expression is a hallmark of the aging process [28]. Growth Differentiation Factor-11 (GDF-11), a member of the transforming growth factor family, has been reported as a rejuvenation factor that reverses age-related decline of tissue functions [29][30][31][32] and is highly expressed in young animals [33]. Sirtuin 1 (SIRT1), an NAD-dependent deacetylase, helps prevent age-related DNA damage and telomere shortening by inducing telomerase reverse transcriptase activity [34,35].…”

Section: Krg Altered Protein Expression But Not Mrna Expression Of Aging-related Genes In Aged Micementioning

confidence: 99%

Korean Red Ginseng Plays an Anti-Aging Role by Modulating Expression of Aging-Related Genes and Immune Cell Subsets

Shin

Kim

et al. 2020

Molecules

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Despite previous reports of anti-aging effects of Korean red ginseng (KRG), the underlying mechanisms remain poorly understood. Therefore, this study investigated possible mechanisms of KRG-mediated anti-aging effects in aged mice. KRG significantly inhibited thymic involution in old mice. Interestingly, KRG only increased protein expression, but not mRNA expression, of aging-related genes Lin28a, GDF-11, Sirt1, IL-2, and IL-17 in the thymocytes of old mice. KRG also modulated the population of some types of immune cells in old mice. KRG increased the population of regulatory T cells and interferon-gamma (IFN-γ)-expressing natural killer (NK) cells in the spleen of old mice, but serum levels of regulatory T cell-specific cytokines IL-10 and TGF-β were unaffected. Finally, KRG recovered mRNA expression of Lin28a, GDF-11, and Sirt1 artificially decreased by concanavalin A (Con A) in both thymocytes and splenocytes of old mice without cytotoxicity. These results suggest that KRG exerts anti-aging effects by preventing thymic involution, as well as modulating the expression of aging-related genes and immune cell subsets.

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“…Collagen II provides tensile strength, and Aggrecan is highly hydrated and thereby allows cartilage to resist a compressive load [ 21 , 22 ]. An increase in these proteins represents a rise in cartilage secretion activity, along with alterations in cartilage cellular function [ 23 ]. Under physiologic conditions, this cartilaginous ECM is constantly remodeled through degradation followed by the synthesis of Collagen II and Aggrecan to maintain the integrity of cartilage.…”

Section: Introductionmentioning

confidence: 99%

Echinacoside Upregulates Sirt1 to Suppress Endoplasmic Reticulum Stress and Inhibit Extracellular Matrix Degradation In Vitro and Ameliorates Osteoarthritis In Vivo

Lin

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. Osteoarthritis (OA) is a progressive illness that destroys cartilage. Oxidative stress is a major contributor of OA, while endoplasmic reticulum (ER) stress is the key cellular damage under oxidative stress in chondrocytes. Echinacoside (ECH) is the main extract and active substance of Cistanche, with potent antioxidative stress (OS) properties, and currently under clinical trials in China. However, its function in OA is yet to be determined. Purpose. We aimed to explore the specific role of ECH in the occurrence and development of OA and its underlying mechanism in vivo and in vitro. Methods. After the mice were anesthetized, the bilateral medial knee joint meniscus resection was performed to establish the DMM model. TBHP was used to induce oxidative stress to establish the OA model in chondrocytes in vitro. Western blot and RT-PCR were used to evaluate the level of ER stress-related biomarkers such as p-PERK/PERK, GRP78, ATF4, p-eIF2α/eIF2α, and CHOP and apoptosis-related proteins such as BAX, Bcl-2, and cleaved caspase-3. Meanwhile, we used SO staining, immunofluorescence, and immunohistochemical staining to evaluate the pharmacological effects of ECH in mice in vivo. Results. We demonstrated the effectiveness of ECH in suppressing ER stress and restoring ECM metabolism in vitro. In particular, ECH was shown to suppress tert-Butyl hydroperoxide- (TBHP-) induced OS and subsequently lower the levels of p-PERK/PERK, GRP78, ATF4, p-eIF2α/eIF2α, and CHOP in vitro. Simultaneously, ECH reduced MMP13 and ADAMTS5 levels and promoted Aggrecan and Collagen II levels, suggesting ECM degradation suppression. Moreover, we showed that ECH mediates its cellular effects via upregulation of Sirt1. Lastly, we confirmed that ECH can protect against OA in mouse OA models. Conclusion. In summary, our findings indicate that ECH can inhibit ER stress and ECM degradation by upregulating Sirt1 in mouse chondrocytes treated with TBHP. It can also prevent OA development in vivo.

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Positive Effects of a Young Systemic Environment and High Growth Differentiation Factor 11 Levels on Chondrocyte Proliferation and Cartilage Matrix Synthesis in Old Mice

Cited by 25 publications

References 40 publications

The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy

The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy

Korean Red Ginseng Plays an Anti-Aging Role by Modulating Expression of Aging-Related Genes and Immune Cell Subsets

Echinacoside Upregulates Sirt1 to Suppress Endoplasmic Reticulum Stress and Inhibit Extracellular Matrix Degradation In Vitro and Ameliorates Osteoarthritis In Vivo

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