Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

Niu, Bo; Wang, Peng; Xinghong, Pei; Kang, Y.; Song, Jun; Wang, Dahui; Zhang, Wanglin; Ma, Rong

doi:10.1007/s00264-011-1315-6

Cited by 16 publications

(21 citation statements)

References 41 publications

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“…Several signaling networks have been identified that can stimulate hypertrophic differentiation of chondrocytes in the growth plate. These networks include the Wnt/β‐catenin (3–5), bone morphogenetic protein (BMP) (6), Indian hedgehog (IHH) (7), and hypoxia‐induced signaling (8) pathways. Forced activation or conditional inactivation of these pathways in articular chondrocytes results in a release of the brake on hypertrophic differentiation and induces the features of OA in mice (9–12).…”

mentioning

confidence: 99%

Gremlin 1, Frizzled‐related protein, and Dkk‐1 are key regulators of human articular cartilage homeostasis

Leijten

Emons

Sticht

et al. 2012

Arthritis & Rheumatism

126

130

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Objective. The development of osteoarthritis (OA) may be caused by activation of hypertrophic differentiation of articular chondrocytes. Healthy articular cartilage is highly resistant to hypertrophic differentiation, in contrast to other hyaline cartilage subtypes, such as growth plate cartilage. The purpose of this study was to elucidate the molecular mechanism responsible for the difference in the propensity of human articular cartilage and growth plate cartilage to undergo hypertrophic differentiation.Methods. Whole-genome gene-expression microarray analysis of healthy human growth plate and articular cartilage derived from the same adolescent donors was performed. Candidate genes, which were enriched in the articular cartilage, were validated at the messenger RNA (mRNA) and protein levels and examined for their potential to inhibit hypertrophic differentiation in two models. In addition, we studied a possible genetic association with OA.Results. Pathway analysis demonstrated decreased Wnt signaling in articular cartilage as compared to growth plate cartilage. This was at least partly due to increased expression of the bone morphogenetic protein and Wnt antagonists Gremlin 1, Frizzledrelated protein (FRP), and Dkk-1 at the mRNA and protein levels in articular cartilage. Supplementation of these proteins diminished terminal hypertrophic differentiation without affecting chondrogenesis in long-bone explant cultures and chondrogenically differentiating human mesenchymal stem cells. Additionally, we found that single-nucleotide polymorphism rs12593365, which is located in a genomic control region of GREM1, was significantly associated with a 20% reduced risk of radiographic hip OA in 2 population-based cohorts.Conclusion. Taken together, our study identified Gremlin 1, FRP, and Dkk-1 as natural brakes on hypertrophic differentiation in articular cartilage. As hypertrophic differentiation of articular cartilage may contribute to the development of OA, our findings may open new avenues for therapeutic intervention.Healthy articular cartilage is largely resistant to hypertrophic differentiation. In contrast, other forms of hyaline cartilage, such as growth plate cartilage, which is responsible for bone elongation via endochondral ossification, naturally undergoes hypertrophic differentiation (1). The molecular mechanism underlying this discrepancy between these two types of hyaline cartilage is largely unknown. It has been postulated that articular cartilage secretes a factor(s) that inhibits chondrocyte

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mentioning

confidence: 99%

Gremlin 1, Frizzled‐related protein, and Dkk‐1 are key regulators of human articular cartilage homeostasis

Leijten

Emons

Sticht

et al. 2012

Arthritis & Rheumatism

126

130

View full text Add to dashboard Cite

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“…While on the other hand, it is harmful to the mature chondrocytes, inducing their apoptosis. Although β -catenin is essential for cartilage differentiation, its overactivation in mature chondrocytes would cause cartilage degeneration, producing KOA chondrocytes [ 30 ]. In this study, the reduced C/ebp α promoter methylation in KOA model rats may induce C/ebp α overexpression, resulting in activation of the Wnt/ β -catenin signaling pathway; the overactivation of β -catenin induces intracellular accumulation of β -catenin, thereby promoting cartilage formation and apoptosis of mature chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Effects of Qi-Fang-Xi-Bi-Granules on Cartilage Morphology and C/ebpαPromoter Methylation in Rats with Knee Osteoarthritis

Wang

Shen

Tang

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Objective To investigate the effects of Qi-Fang-Xi-Bi-Granules (QFXBGs) on cartilage morphology and methylation of C/ebpα (CCAAT/enhancer binding proteinα) at the promoter region. Methods Knee osteoarthritis (KOA) modeling was performed in rats in accordance with Hulth's method, and control group received sham operation. Eight weeks after KOA modeling, the rats in the KOA modeling group were further divided into 6 groups. Each group was given the appropriate drug. After 8 weeks, half of the rats were used for Micro-CT scan, HE staining, ABH/OG staining, immunohistochemistry, and TUNNEL staining of the knee joint tissue, and the other half were used to examine C/ebpα promoter methylation. Results The three dose groups of QFXBGs all showed lower degrees of surface fissures and flaking, thicker cartilage layer, and restored chondrocyte and subchondral bone morphology, compared with the KOA model group. C/ebpα-22 promoter methylation levels in the high- and low-dose groups were significantly higher than that in the KOA modeling group (p < 0.05), while C/ebpα-2 promoter methylation level in the medium-dose group was significantly higher than that in the KOA modeling group (p < 0.05). Conclusions QFXBGs may alleviate articular cartilage degeneration through promoting C/ebpα-2 or C/ebpα-22 methylation at specific promoter sites.

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“…If the Wnt signaling pathway is inhibited, embryonic development will gradually be disrupted resulting in mutated phenotypes, such as the Wnt3 mutation that causes head deformities, or lack of (short) limb deformities (38). In addition, a previous study demonstrated that induction of the downstream components of the Wnt/β-catenin signaling pathway, including inhibitor of bone morphology proteins and DKK-1 proteins, induces cell apoptosis, which in turn leads to birth defects (39). The results of the present study demonstrated that the protein expression levels of β-catenin and DKK-1 were markedly increased following BPA treatment, in a dose-dependent manner, as compared with the control group.…”

Section: Discussionmentioning

confidence: 99%

Effects of Wnt/β-catenin signaling on bisphenol A exposure in male mouse reproductive cells

Fang

Liu

Yang

et al. 2015

Molecular Medicine Reports

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Bisphenol A (BPA) is a chemical used in numerous consumer products that is able to interfere with the mammalian endocrine system. The aim of the present study was to investigate the effects of BPA on male mouse reproductive cells following prenatal to postnatal exposure. In addition, the influence of BPA was detected on the expression levels of β‑catenin and dickkopf WNT signaling pathway inhibitor 1 (DKK‑1) during the differentiation of spermatogenic cells in the mouse testes. β‑catenin and DKK‑1 are two important proteins of the Wnt/β‑catenin signaling pathway. On gestational day 1, pregnant ICR mice were randomly divided into four groups: A dimethyl sulfoxide group, and three groups treated with various concentrations of BPA (0.5, 10, and 50 µg/kg). BPA was administered from gestational day 1 to weaning on postnatal day (PND) 42. The number of murine pups and the male:female ratio was recorded for each group. On PND 42, the male pups were sacrificed and their wet weights and testicular coefficients were measured. Immunohistochemical and western blot analyses were used to detect the protein expression of β‑catenin and DKK‑1 in the testicular tissue samples of the six‑week‑old male mice. The results indicated that the number of murine pups, as well as the testicular viscera coefficient of the male mice, significantly decreased in the BPA‑treated groups, as compared with the control group (P<0.05, P<0.01); however, no significant difference was observed in the male/female ratio in the BPA‑treated groups, as compared with the control group (P>0.05). The results from the immunohistochemical and western blot analyses indicated that the protein expression of β‑catenin and DKK‑1 were significantly increased in the BPA‑treated groups, as compared with the control group, and the distribution of spermospore and Leydig cells also increased in the testes. These results suggest that high expression levels of β‑catenin and DKK‑1 may participate in BPA‑induced pathogenesis in male mouse reproductive cells.

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Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

Cited by 16 publications

References 41 publications

Gremlin 1, Frizzled‐related protein, and Dkk‐1 are key regulators of human articular cartilage homeostasis

Gremlin 1, Frizzled‐related protein, and Dkk‐1 are key regulators of human articular cartilage homeostasis

Effects of Qi-Fang-Xi-Bi-Granules on Cartilage Morphology and C/ebpαPromoter Methylation in Rats with Knee Osteoarthritis

Effects of Wnt/β-catenin signaling on bisphenol A exposure in male mouse reproductive cells

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