A possible mechanism in DHEA-mediated protection against osteoarthritis

Li, Weijun; Tang, Luping; Xiong, Yan; Chen, Weiping; Zhou, Xindie; Ding, Qianhai; Wu, Lidong

doi:10.1016/j.steroids.2014.07.011

Cited by 17 publications

(9 citation statements)

References 24 publications

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“…The upregulation of β-catenin in degraded cartilage indicated that the stimulation of the Wnt signaling pathway led to cartilage loss (32). In addition, in animal models of OA, β-catenin was found to be overexpressed in articular cartilage (33). In the present study, TNF-α treatment increased the expression levels of Wnt-3a and nuclear β-catenin in the chondrocytes.…”

Section: Discussionsupporting

confidence: 53%

Vitamin D3 protects articular cartilage by inhibiting the Wnt/β‑catenin signaling pathway

Yang¹,

Sun

Duan³

et al. 2020

Exp Ther Med

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Low expression levels of 25-hydroxyvitamin D (vitamin D3) in the blood have been reported to be associated with the progression of osteoarthritis; however, the mechanisms by which this occurs remain unclear. The present study aimed to determine the effects of vitamin D3 on chondrocytes. MTT assays were used to determine whether vitamin D3 affects chondrocytes viability. Primary chondrocytes were treated with control culture medium, vitamin D3, tumor necrosis factor (TNF)-α, TNF-α + PNU-74654 [Wingless-related integration site (Wnt)/β-catenin signaling pathway inhibitor] or TNF-α + vitamin D3. Reverse transcription-quantitative PCR and western blotting were utilized to measure the gene and protein expression of collagen II, aggrecan, matrix metalloproteinase (MMP)-3 and MMP-13, A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, Wnt-3a and nuclear β-catenin. The results demonstrated that TNF-α reduced the expression levels of aggrecan and collagen II, and increased the expression levels of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5. Furthermore, vitamin D3 and PNU-74654 were observed to partially attenuate the effects induced by TNF-α. Moreover, similar findings were reported following co-treatment with vitamin D3 and TNF-α. Western blotting data revealed that TNF-α increased Wnt-3a and β-catenin protein levels in chondrocytes, while Vitamin D3 and PNU-74654 decreased the expression levels of Wnt-3a and nuclear β-catenin. In conclusion, the findings of the present study provided evidence to suggest that vitamin D3 may prevent articular cartilage degeneration and osteoarthritic disease progression by inhibiting the expression levels of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 through suppressing the Wnt/β-catenin signaling pathway. These results suggested that vitamin D3 may be of therapeutic value for the prevention and treatment of osteoarthritis.

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Section: Discussionsupporting

confidence: 53%

Vitamin D3 protects articular cartilage by inhibiting the Wnt/β‑catenin signaling pathway

Yang¹,

Sun

Duan³

et al. 2020

Exp Ther Med

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“…The results of the two studies suggest that Wnt/β-catenin signaling activation is enhanced in advanced OA with severe joint damage compared with the early and middle stages of the disease. Moreover, our most recent study [ 26 ] demonstrated that DHEA likely exerts its anti-osteoarthritic effect by regulating Wnt/β-catenin signaling. The protective effect of DHEA was significantly decreased when Wnt/β-catenin signaling was activated, whereas the inactivation of Wnt/β-catenin signaling enhanced the effects of DHEA.…”

Section: Discussionmentioning

confidence: 99%

The disease-modifying effect of dehydroepiandrosterone in different stages of experimentally induced osteoarthritis: a histomorphometric study

Huang

Bao

Jennings

et al. 2015

BMC Musculoskelet Disord

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BackgroundOsteoarthritis (OA) is likely to become an increasing burden in the coming decades. Various agents have been developed to slow the progression of OA, and are collectively known as ‘disease-modifying drugs’, however, there is still little reliable evidence that such agents will be successful. Dehydroepiandrosterone (DHEA), a sex hormone precursor, has been recently proven as protective agent against OA, but the exact mechanism is still unkown. In the current study, the effects of weekly intra-articular injections of DHEA in preventing the progression of existing cartilage degeneration in an OA rabbit model were evaluated. The aim of the current study is to demonstrate the feature of its disease-modifying efficacy during OA progression.MethodsThirty male New Zealand white rabbits were used in this study. An anterior cruciate ligament transection (ACLT) model was used to create a progressive OA model in twenty rabbits. The animals were treated with DHEA or a placebo and were necropsied at 9 and 16 weeks. Ten rabbits receiving sham operations served as controls. The articular cartilage of the medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibial plateau (MTP) and lateral tibial plateau (LTP) was evaluated macroscopically and histologically.ResultsIn the joints of the sham-operated rabbits, few histological changes were detected on the articular surfaces of the femoral condyles and tibial plateaus. ACLT obviously induced erosive changes on the cartilage surfaces. Compared to the placebo group, the macroscopic and Mankin score analyses demonstrated that the DHEA treatment markedly reduced the cartilage lesions and delayed cartilage degeneration in the four regions of the knee at 9 weeks after operation (macroscopic score: MFC P = 0.013; LFC P = 0.048; MTP P = 0.045; LTP P = 0.02, Mankin score: MFC P = 0.012; LFC P = 0.034; MTP P = 0.016; LTP P = 0.002). At 16 weeks, DHEA demonstrated chondroprotective effects on the lateral compartment of the knee compared to the placebo group, whereas the cartilage degeneration at the medial compartment of the knee did not differ among the groups (macroscopic score: LFC P = 0.046; LTP = 0.034, Mankin score: LFC P = 0.005; LTP P = 0.002).ConclusionThe disease-modifying efficacy of DHEA aganist OA is time-specific and site-dependent. DHEA could be used as a disease-modifying strategy to limit the progression of OA, especially in the middle stage.

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“…β-catenin plasmid construction was performed based on a previous study ( 19 ). The β-catenin gene was ligated into the pTagRFP eukaryotic expression vector (Evrogen JSC).…”

Section: Methodsmentioning

confidence: 99%

“…Rabbits were divided into three groups (n=4 in each group). Anterior cruciate ligament transaction of bilateral knee joints was performed in each rabbit according to a previous study (19). The rabbits were housed under standard conditions for four weeks following the operation, and 0.3 ml DKK1, LiCl and vehicle (PBS) were injected respectively into the knee joint once every week.…”

Section: Treatment Of Rat Chondrocytes With Wnt-1 and Il-1βmentioning

confidence: 99%

Wnt/β‑catenin signaling may induce senescence of chondrocytes in osteoarthritis

Xiong

Chen

et al. 2020

Exp Ther Med

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Osteoarthritis (OA) is an autoimmune disease associated with increasing age. Typically, chondrocyte senescence is believed to serve an important role in the development and progression of OA. However, the specific mechanisms underlying chondrocyte senescence have not been fully addressed. The present study hypothesized that the Wnt/β-catenin signaling may represent a major regulator of chondrocyte senescence. In addition, the acetylated levels of p53 and sirtuin-1 (SIRT-1) were examined as putative markers for chondrocyte senescence, since activation of p53 is considered an important step in the regulation of senescence. The Wnt/β-catenin signaling pathway was activated using LiCl and inhibited using the Wnt signaling pathway inhibitor, dickkopf-1 (DKK1) in order to evaluate the role of this pathway in the development of OA. Senescent cells were detected using the senescence-associated indicator acidic senescence-associated β-galactosidase (SA-β-gal). The effects of p53 and p16 on chondrocyte senescence were assessed via activation of Wnt/β-catenin signaling using Wnt-1. In addition, β-catenin was transfected into chondrocytes to induce activation of the Wnt/β-catenin signaling pathway. Finally, a rabbit model of OA was used to assess whether the observed effects on the Wnt/β-catenin signaling pathway and the induction of chondrocyte senescence were perpetuated. Activation of Wnt/β-catenin signaling increased the expression levels of SA-β-gal, p53, p16 and acetylated p53. Transfection of β-catenin in chondrocytes increased the expression levels of acetylated p53 and decreased the expression levels of SIRT-1, which in turn deacetylated p53 and modulated its activity. Finally, the role of the Wnt/β-catenin signaling pathway was confirmed in the development of OA using a rabbit model with this condition. The present study suggested that activation of the Wnt/β-catenin signaling pathway promoted chondrocyte senescence, through downregulation of SIRT-1 and increased the expression of acetylated p53.

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A possible mechanism in DHEA-mediated protection against osteoarthritis

Cited by 17 publications

References 24 publications

Vitamin D3 protects articular cartilage by inhibiting the Wnt/β‑catenin signaling pathway

Vitamin D3 protects articular cartilage by inhibiting the Wnt/β‑catenin signaling pathway

The disease-modifying effect of dehydroepiandrosterone in different stages of experimentally induced osteoarthritis: a histomorphometric study

Wnt/β‑catenin signaling may induce senescence of chondrocytes in osteoarthritis

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