ANGPTL2 Promotes Inflammation via Integrin α5β1 in Chondrocytes

Takano, Mami; Hirose, Naoto; Sumi, Chikako; Yanoshita, Makoto; Nishiyama, Sayuri; Onishi, Azusa; Asakawa, Yuki; Tanimoto, Kotaro

doi:10.1177/1947603519878242

Cited by 18 publications

(17 citation statements)

References 50 publications

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“…This cell line presented more similar behavior to human primary chondrocytes in response to pro-inflammatory stimulus than other chondrogenic cell lines. 18,19 First, we observed that IL-1α, a well-known potent inducer of MMP-13, repressed DKK3 expression in chondrocytes, as previously described. 12 Thus, by silencing DKK3 gene, we demonstrated for the first time that DKK3 is acting as a MMP-13 down-modulator in the context of pro-inflammatory cytokine induction, in both human primary chondrocytes and murine ATDC5 cells.…”

Section: Discussionsupporting

confidence: 77%

Dickkopf-3 (DKK3) Signaling in IL-1α-Challenged Chondrocytes: Involvement of the NF-κB Pathway

et al. 2020

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Objective Osteoarthritis (OA) is an age-related biomechanical and low-grade inflammometabolic disease of the joints and one of the costliest and disabling forms of arthritis. Studies on matrix-degrading enzymes such as metalloproteases, which are implicated in the increased catabolism of extracellular matrix, are of paramount relevance. DKK3 is a member of DKK family and is best known for its role in cancer. Although there is some information about the participation of DKK3 in cartilage pathophysiology and on metalloproteases regulation, in particular, little is known about DKK3 signaling mechanisms. Thus, the aim of this study is to explore how DKK3 regulates matrix metalloproteinase-13 (MMP-13) expression. Design Gene, protein expression and protein phosphorylation in primary human chondrocytes and ATDC5 mouse cells were assessed by RT-qPCR and Western blot analysis. Further studies on DKK3 activity were performed by targeting DKK3 gene with a specific siRNA. Results DKK3 expression was found to be higher in OA human chondrocytes than healthy cells, being its expression decreased in interleukin-1α (IL-1α)-stimulated cells. DKK3 knockdown increased the induction of MMP-13 elicited by IL-1α in human and mouse chondrocytes and after the analysis of different signalling pathways, we observed that NF-κB pathway was involved in the regulation of MMP-13 expression by DKK3. Conclusions Herein we have demonstrated, for the first time, that DKK3 gene silencing exacerbated NF-κB activation, resulting in an increased IL-1α-driven induction of MMP-13. Our results further confirm that DKK3 may play a protective role in OA by attenuating NF-κB activation and the subsequent production of metalloproteases.

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Section: Discussionsupporting

confidence: 77%

Dickkopf-3 (DKK3) Signaling in IL-1α-Challenged Chondrocytes: Involvement of the NF-κB Pathway

et al. 2020

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“…This medium induced chondrogenic differentiation, as described previously (Atsumi et al, 1990;Altaf et al, 2006). In our protocol, the gene expression of type II collagen was upregulated strongly 14 days after differentiation induction, however, that of type X collagen was not upregulated yet in ATDC5 Takano et al, 2019). Therefore, we defined the 14-day differentiated ATDC5 as that on the extracellular matrix production stage.…”

Section: Cell Culturementioning

confidence: 93%

Protective effects of cilengitide on inflammation in chondrocytes under excessive mechanical stress

Hirose

Okamoto

Yanoshita

et al. 2020

Cell Biology International

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Chondrocytes constantly receive external stimuli, which regulates remodeling. An optimal level of mechanical stress is essential for maintaining chondrocyte homeostasis, however, excessive mechanical stress induces inflammatory cytokines and protease, such as matrix metalloproteinases (MMPs). Therefore, excessive mechanical stress is considered to be one of the main causes to cartilage destruction leading to osteoarthritis (OA). Integrins are well‐known as cell adhesion molecules and act as receptors for extracellular matrix (ECM), and are believed to control intracellular signaling pathways both physically and chemically as a mechanoreceptor. However, few studies have focused on the roles and functions of integrins in inflammation caused by excessive mechanical stress. In this study, we examined the relationship between integrins (αVβ3 and αVβ5) and the expression of inflammatory factors under mechanical loading in chondrocytes by using an integrin receptor antagonist (cilengitide). Cilengitide suppressed the gene expression of interleukin‐1β (IL‐1β), tumor necrosis factor‐α (TNF‐α), matrix metalloproteinase‐3 (MMP‐3), and MMP‐13 induced by excessive mechanical stress. In addition, the protein expression of IL1‐β and MMP‐13 was also inhibited by the addition of cilengitide. Next, we investigated the involvement of intracellular signaling pathways in stress‐induced integrin signaling in chondrocytes by using western blotting. The levels of p‐FAK, p‐ERK, p‐JNK, and p‐p38 were enhanced by excessive mechanical stress and the enhancement was suppressed by treatment with cilengitide. In conclusion, this study revealed that excessive mechanical stress may activate integrins αVβ3 and αVβ5 on the surface of chondrocytes and thereby induce an inflammatory reaction by upregulating the expression of IL‐1β, TNF‐α, MMP‐3, and MMP‐13 through phosphorylation of FAK and MAPKs.

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“…Total RNA was extracted from each specimen, and cDNA was obtained by reverse transcription (RT) according to previously described methods [ 36 ]. Real-time quantitative RT-PCR was used to evaluate the expression of the following cartilage-specific genes: type II collagen (COL II) a1, Sox-9, aggrecan, and hypertrophic genes: RUNX2, type X collagen (COL X) a1, and MMP13.…”

Section: Methodsmentioning

confidence: 99%

Hypoxic ADSCs-derived EVs promote the proliferation and chondrogenic differentiation of cartilage stem/progenitor cells

et al. 2021

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Cartilage tissue engineering is a promising option for repairing cartilage defects, although harvesting a large number of seeding cells remains a major challenge. Cartilage stem/progenitor cells (CSPCs) seem to be a promising cell source. Hypoxic extracellular vesicles (EVs) may play a major role in cell-cell and tissue-tissue communication. In the current study, we aimed to evaluate the effect of hypoxic adipose-derived stem cells (ADSCs)-derived EVs on CSPCs proliferation and differentiation. The characteristics of ADSCs-derived EVs were identified, and proliferation, migration, and cartilage-related gene expression of CSPCs were measured with or without the presence of hypoxic ADSCs-derived EVs. SEM, histological staining, biochemical and biomechanical analysis was performed to evaluate the effect of hypoxic ADSCs-derived EVs on CSPCs in alginate hydrogel culture. The results indicated that the majority of ADSC-derived EVs exhibited a round-shaped or cup-shaped morphology with a diameter of 40-1000 nm and expressed CD9, CD63, and CD81. CSPCs migration and proliferation were enhanced by hypoxic ADSCs-derived EVs, which also increased the expression of cartilage-related genes. The hypoxic ADSCs-derived EVs induce CSPCs to produce significantly more cartilage matrix and proteoglycan. In conclusion, hypoxic ADSCsderived EVs improved the proliferation and chondrogenic differentiation of CSPCs for cartilage tissue engineering.

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ANGPTL2 Promotes Inflammation via Integrin α5β1 in Chondrocytes

Cited by 18 publications

References 50 publications

Dickkopf-3 (DKK3) Signaling in IL-1α-Challenged Chondrocytes: Involvement of the NF-κB Pathway

Dickkopf-3 (DKK3) Signaling in IL-1α-Challenged Chondrocytes: Involvement of the NF-κB Pathway

Protective effects of cilengitide on inflammation in chondrocytes under excessive mechanical stress

Hypoxic ADSCs-derived EVs promote the proliferation and chondrogenic differentiation of cartilage stem/progenitor cells

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