Epigenetic Regulation of Chondrocytes and Subchondral Bone in Osteoarthritis

Ball, Hope C.; Alejo, Andrew; Samson, Trinity K; Alejo, Amanda M.; Safadi, Fayez F.

doi:10.3390/life12040582

Cited by 10 publications

(6 citation statements)

References 284 publications

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“…Virtual screening of potentially active constituents targeting DNMT1 from DD DNMT1-mediated hypermethylation of PPARγ promoter in chondrocytes is a key mechanism for promoting OA (Ball et al, 2022). To identify the active constituents of DD for the treatment of OA by targeting DNMT1, 906 constituents from DD were docked into the pocket for DNMT1.…”

Section: Results and Disussion Dd Alleviated Tibial Subchondral Bone ...mentioning

confidence: 99%

Deciphering the active constituents of Dabushen decoction of ameliorating osteoarthritis via PPARγ preservation by targeting DNMT1

Qiu

Zhang

et al. 2022

Front. Pharmacol.

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Osteoarthritis (OA) is a multifactorial and chronic degenerative joint disease. Due to the adverse effects of currently used drugs, a safer and more effective therapy for treating OA is needed. Peroxisome proliferator-activated receptor-γ (PPARγ) is a key protein protecting cartilage. DNMT1-mediated hypermethylation of PPARγ promoter leads to its suppression. Therefore, DNMT1 might be an effective target for exerting cartilage protective effects by regulating the epigenetic expression of PPARγ. Dabushen decoction (DD) is a representative prescription of Dunhuang ancient medical prescription, which has a potential therapeutic effect on OA. So far, the research of the efficacy and material basis of DD in the treatment of OA remains unclear. In this study, Micro-CT, HE staining, S-O staining, and immunohistochemistry analysis were used to demonstrate that DD increased the expression of PPARγ and collagen synthesis in an OA rat model. Next, the structure of DNMT1 was used to screen the active constituents of DD by molecular docking method for treatment OA. Seven potential active constituents, including isoliquiritigenin, emodin, taxifolin, catalpol, alisol A, zingerone, and schisandrin C were hited. The protective effect of the potential active constituents to chondrocytes were evaluated by protein capillary electrophoresis, immunofluorescence assays, and ex vivo culture of rat knee cartilage. The five constituents, such as alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C could promote the expression of PPARγ and ameliorate IL-1β-induced downregulation of collagen II and the production of MMP-13. Alisol A and Emodin could effectively mitigate cartilage damage. At last, molecular dynamics simulations with MM-GBSA method was applied to investigate the interaction pattern of the active constituents and DNMT1 complexes. The five constituents, such as alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C achieved a stable binding pattern with DNMT1, in which alisol A has a relatively high binding free energy. In conclusion, this study elucidates that the active constituents of DD (alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C) could ameliorate osteoarthritis via PPARγ preservation by targeting DNMT1.These findings facilitated clinical use of DD and provided a valuable strategy for developing natural epigenetic modulators from Chinese herbal formula.

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Section: Results and Disussion Dd Alleviated Tibial Subchondral Bone ...mentioning

confidence: 99%

Deciphering the active constituents of Dabushen decoction of ameliorating osteoarthritis via PPARγ preservation by targeting DNMT1

Qiu

Zhang

et al. 2022

Front. Pharmacol.

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“…Osteoarthritis (OA) is a degenerative joint disease that results in cartilage damage and chronic pain and disability in those affected [66,67]. Known risk factors include age, obesity, traumatic or developmental joint instability, chronic inflammatory conditions, and modulation of epigenetic regulation [10,[68][69][70]. Studies have shown that inflammation plays a key role in the onset and progression of OA through increased expression of matrix proteases and stimulation of chondrocyte hypertrophy and apoptosis [15,71].…”

Section: Discussionmentioning

confidence: 99%

“…OA is a whole joint disease that results in chronic inflammation, cartilage degradation, abnormal subchondral bone remodeling, osteophyte formation, synovitis, and fibrosis of the infrapatellar fat pad [4][5][6][7][8]. Articular chondrocytes are the primary cell type present in cartilage and are responsible for secretion and homeostasis of an extracellular matrix (ECM) composed of collagen type-II-α (Col2α) and proteoglycans [9][10][11][12]. When damaged, chondrocytes are unable to repair the damage and contribute to degradation by undergoing cellular hypertrophy and apoptosis and increasing production of matrix-degrading proteases, such as matrix metalloproteinases (MMPs), responsible for breakdown of the collagenous and non-collagenous cartilage matrix components [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

TRAPPC9 Modulation Regulates IL-1β-Induced Chondrocyte Inflammation

Hussein¹,

Alejo²,

Prior³

et al. 2023

Preprint

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Osteoarthritis (OA) is a debilitating degenerative joint disease that results in chronic pain and inflammation due to progressive mechanical and proteolytic cartilage degradation. Articular chondrocytes, the main cell type present in cartilage, are responsible for the deposition and maintenance of the cartilage extracellular matrix (ECM). However, following damage and inflammation, chondrocytes undergo hypertrophy, apoptosis, and contribute to inflammation and ECM degradation. NF-κB signaling is known to be dysregulated in OA. TRAPPC9, a vesicle trafficking protein, is known to directly activate NF-κB signaling in neuronal and bone cells, however, the biological significance of this protein in chondrocytes has yet to be elucidated. Here, we demonstrate that TRAPPC9 enhances pro-inflammatory gene and protein expression in murine primary articular chondrocytes. Furthermore, we show that TRAPPC9 elicits these responses via phosphorylation of P-100 that activates non-canonical NF-κB signaling. Taken together, these findings suggest TRAPPC9 may be a potential therapeutic target to decrease inflammation and matrix degradation during OA pathology.

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“…Primary OA is more prevalent and is a result of aging, whereas secondary OA is caused by joint trauma or other illness [3]. OA can be regarded as a multifactorial disease, with several factors including aging, genetic predisposition, epigenetic control, inflammation, obesity, and trauma being involved in its pathophysiology [4].…”

Section: Introductionmentioning

confidence: 99%

Relation of STAT3 rs1053005 Variation and miR-452-3p with Osteoarthritis Susceptibility and Severity and the Clinical Response to High-Molecular-Weight Hyaluronic Acid Injection in Osteoarthritis Patients

Wahba,

Mohamed,

Mehanna

et al. 2023

Diagnostics

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Polymorphisms in the 3′ untranslated region of STAT3 mRNA can derange STAT3 gene expression via modifying the microRNA-binding site. This study aimed to examine the impact of STAT3 rs1053005 variation and miR-452-3p expression on osteoarthritis (OA) susceptibility and severity and the efficacy of intra-articular high-molecular-weight hyaluronic acid (HMW-HA) injection as a therapy option for knee OA. Two hundred and fifty-eight OA patients and 200 healthy controls were enrolled in the study. STAT3 genotyping and STAT3 and miR-452-3p expression were carried out using allelic-discrimination PCR and quantitative real-time PCR. Functional assessment and pain evaluation were performed for all patients. Eighty-three patients received HMW-HA injections, and multiple follow-up visits were performed. STAT3 mRNA was upregulated, and expression was positively associated with plasmin, TNF-α, MMP-3, and STAT3 serum levels, whereas miR-452-3p was downregulated and negatively associated with the previously mentioned parameters in OA patients. Osteoarthritis patients had a lower prevalence of the minor allele of the rs1053005 variant (p < 0.001). Plasmin, TNF, MMP-3, and STAT3 mRNA and protein levels were significantly decreased, and miR-452-3p expression was significantly increased in the GG genotype compared to AG and AA genotypes. HMW-HA injection improved OA patients’ clinical scores with concomitant decreased STAT3 levels and enhanced expression of miR-452-3p. More efficient improvement was observed in rs1053005 AG + GG genotype carriers vs. AA genotype carriers. The G allele of STAT3 rs1053005 (A/G) polymorphism was associated with decreased OA susceptibility and severity and enhanced clinical response to HMW-HA injection, possibly via enhancing miR-452-3p binding and a subsequent decrease in STAT3 expression.

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Epigenetic Regulation of Chondrocytes and Subchondral Bone in Osteoarthritis

Cited by 10 publications

References 284 publications

Deciphering the active constituents of Dabushen decoction of ameliorating osteoarthritis via PPARγ preservation by targeting DNMT1

Deciphering the active constituents of Dabushen decoction of ameliorating osteoarthritis via PPARγ preservation by targeting DNMT1

TRAPPC9 Modulation Regulates IL-1β-Induced Chondrocyte Inflammation

Relation of STAT3 rs1053005 Variation and miR-452-3p with Osteoarthritis Susceptibility and Severity and the Clinical Response to High-Molecular-Weight Hyaluronic Acid Injection in Osteoarthritis Patients

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