Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

Rodríguez-Trillo, Ángela; Mosquera, Nerea; Pena, Carmen; Rivas-Tobío, Fatima; Varela, A. Mera; González, Antonio; Conde, Carmen

doi:10.3389/fimmu.2020.555245

Cited by 31 publications

(20 citation statements)

References 69 publications

(94 reference statements)

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“…Notably, the expression of Sox9, a key transcription factor related to cartilage formation, and Col-2, returned to the baseline levels after Vangl2 silencing. Our finding that Wnt5a promotes inflammation via multiple pathways in OA chondrocytes is consistent with the results reported before [ 9 , 30 , 31 ]. These data show that all three MAPK pathways (p38, ERK, JNK) can be activated by Wnt5a in OA chondrocytes.…”

Section: Discussionsupporting

confidence: 93%

Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes

Zhang

et al. 2021

J Orthop Surg Res

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Background The Wnt planar cell polarity (PCP) pathway is implicated in osteoarthritis (OA) both in animals and in humans. Van Gogh-like 2 (Vangl2) is a key PCP protein that is required for the orientation and alignment of chondrocytes in the growth plate. However, its functional roles in OA still remain undefined. Here, we explored the effects of Vangl2 on OA chondrocyte in vitro and further elucidated the molecular mechanism of silencing Vangl2 in Wnt5a-overexpressing OA chondrocytes. Methods Chondrocytes were treated with IL-1β (10 ng/mL) to simulate the inflammatory microenvironment of OA. The expression levels of Vangl2, Wnt5a, MMPs, and related proinflammatory cytokines were measured by RT-qPCR. Small interfering RNA (siRNA) of Vangl2 and the plasmid targeting Wnt5a were constructed and transfected into ATDC5 cells. Then, the functional roles of silencing Vangl2 in the OA chondrocytes were investigated by Western blotting, RT-qPCR, and immunocytochemistry (ICC). Transfected OA chondrocytes were subjected to Western blotting to analyze the relationship between Vangl2 and related signaling pathways. Results IL-1β induced the production of Vangl2, Wnt5a, and MMPs in a time-dependent manner and the significantly increased expression of Vangl2. Vangl2 silencing effectively suppressed the expression of MMP3, MMP9, MMP13, and IL-6 at both gene and protein levels and upregulated the expression of type II collagen and aggrecan. Moreover, knockdown of Vangl2 inhibited the phosphorylation of MAPK signaling molecules (P38, ERK, and JNK) and P65 in Wnt5a-overexpressing OA chondrocytes. Conclusions For the first time, we demonstrate that Vangl2 is involved in the OA process. Vangl2 silencing can notably alleviate OA progression in vitro by inhibiting the expression of MMPs and increasing the formation of the cartilage matrix and can inhibit the proinflammatory effects of Wnt5a via MAPK and NF-κB pathway. This study provides new insight into the mechanism of cartilage inflammation.

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Section: Discussionsupporting

confidence: 93%

Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes

Zhang

et al. 2021

J Orthop Surg Res

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“…Notably, the expression of Sox9, a key transcription factor related to cartilage formation, and Col-2, returned to the baseline levels after Vangl2 silencing. Our nding that Wnt5a promotes in ammation via multiple pathways in OA chondrocytes is consistent with the results reported before [9,30,31]. These data show that all three MAPK pathways (p38, ERK, JNK) can be activated by Wnt5a in OA chondrocytes.…”

Section: Discussionsupporting

confidence: 93%

Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes.

Zhang

et al. 2021

Preprint

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Background: The Wnt planar cell polarity (PCP) pathway is implicated in osteoarthritis (OA) both in animals and in humans. Van Gogh-like 2 (Vangl2) is a key PCP protein that is required for the orientation and alignment of chondrocytes in the growth plate. However, its functional roles in OA still remain undefined. Here, we explored the effects of Vangl2 on OA chondrocyte in vitro, and further elucidated the molecular mechanism of silencing Vangl2 in Wnt5a-overexpressing OA chondrocytes.Methods: Chondrocytes were treated with IL-1β (10 ng/mL) to simulate the inflammatory microenvironment of OA. The expression levels of Vangl2, Wnt5a, MMPs, and related proinflammatory cytokines were measured by RT-qPCR. Small interfering RNA (siRNA) of Vangl2 and the plasmid targeting Wnt5a were constructed and transfected into ATDC5 cells. Then the functional roles of silencing Vangl2 in the OA chondrocytes were investigated by Western blotting, RT-qPCR, and immunocytochemistry (ICC). Transfected OA chondrocytes were subjected to Western blotting to analyze the relationship between Vangl2 and related signaling pathways. Results: IL-1β induced the production of Vangl2, Wnt5a and MMPs in a time-dependent manner and the significantly increased expression of Vangl2. Vangl2 silencing effectively suppressed the expression of MMP3, MMP9, MMP13 and IL-6 at both gene and protein levels, and upregulated the expression of type II collagen and aggrecan. Moreover, knockdown of Vangl2 inhibited the phosphorylation of MAPK signaling molecules (P38, ERK, and JNK) and P65 in Wnt5a-overexpressing OA chondrocytes.Conclusions: For the first time, we demonstrate that Vangl2 is involved in the OA process. Vangl2 silencing can notably alleviate OA progression in vitro by inhibiting the expression of MMPs and increasing the formation of the cartilage matrix, and can inhibit the proinflammatory effects of Wnt5a via MAPK and NF-κB pathway. This study provides new insight into the mechanism of cartilage inflammation.

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“…dMM surgery was used to generate a mechanical OA model. during joint degeneration, especially that of the cartilage, the levels of some inflammatory cytokines, (including TNF-α and IL-1β) are increased, and subsequently cause a progressive, cell-mediated cascade of molecular and structural deterioration (36,37). TNF-α and IL-1β exert their detrimental functions via multiple important intracellular cascades, such as the NF-κB and MAPK pathways (38,39), In general, TNF-α and IL-1β transmit inflammatory signals via their receptors and activate the phosphorylation of the IKK complex (40), which then phosphorylates IκBα (41).…”

Section: Discussionmentioning

confidence: 99%

Curcumenol mitigates chondrocyte inflammation by inhibiting the NF‑κB and MAPK pathways, and ameliorates DMM‑induced OA in mice

et al. 2021

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At present, an increasing number of individuals are affected by osteoarthritis (OA), resulting in a heavy socioeconomic burden. OA in knee joints is caused by the release of inflammatory cytokines and subsequent biomechanical and structural deterioration. To determine its anti-inflammatory function, the current study investigated the use of the plant-derived medicine, curcumenol, in OA treatment. curcumenol was not cytotoxic to ATdc5 chondrocytes and primary chondrocytes, as determined using a cell viability test. When these cells were treated with TNF-α and IL-1β to induce inflammation, curcumenol treatment inhibited the progression of inflammation by inactivating the NF-κB and MAPK signaling pathways, as well as decreasing the expression levels of MMP3 (as indicated by reverse transcription-quantitative PcR and western blotting). Moreover, to analyze metabolic and catabolic status in high-density and pellet culture, catalytic changes and the degradation of the extracellular matrix induced by TNF-α and IL-1β, were evaluated by alcian blue staining. These catalytic deteriorations were ameliorated by curcumenol. Using curcumenol in disease management, the mechanical and metabolic disruption of cartilage caused in the destabilization of medial meniscus (dMM) model was prevented in vivo. Thus, curcumenol mitigated inflammation in ATdc5 chondrocytes and primary mice chondrocytes, and also ameliorated OA in a dMM-induced mouse model.

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Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

Cited by 31 publications

References 69 publications

Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes

Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes

Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes.

Curcumenol mitigates chondrocyte inflammation by inhibiting the NF‑κB and MAPK pathways, and ameliorates DMM‑induced OA in mice

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