Notch1-ADAM8 positive feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression

Abstract

BackgroundOsteoarthritis (OA) is one of the most prevalent joint disease, and there are still no effective therapeutic agents or clinical methods for the cure of this disease to date. The degradation of cartilage extracellular matrix (ECM) is a major cause of OA.MethodIL-1β was used to induce chondrogenic degradation. Q-PCR and Western blotting were used to detect mRNA and protein level, respectively. ELISA was used to detect the secreted TNF-α and IL-6 level. Immunofluorescence was used to detect the protein level of Aggrecan, Collagen II and ki67. TUNEL and flow cytometry were used to examine cell apoptosis of chondrocytes. ChIP and luciferase assay were used to study molecular gene regulation. Osteoarthritic animal model and Safranin-O staining were used to determine the in vivo OA phenotype.ResultsThe expression of ADAM8 was up-regulated in osteoarthritic chondrocytes. Knockdown of ADAM8 suppressed the OA phenotype in the in vitro OA cell model. ADAM8 regulated OA progression through the activation of EGFR/ERK/NF-κB signaling pathway. Inhibition of Notch signaling suppressed OA phenotype in the in vitro OA cell model. Notch signaling regulated the gene expression of ADAM8 directly via Hes1. Notch1-ADAM8 positive feedback loop promoted the progression of OA in vivo.ConclusionNotch1-ADAM8 feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression.

RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4‐mediated ubiquitination of HES1

“…The observation that HES1 mRNA levels follow the HES1 protein stabilization pattern after RASSF1A modulation (Fig 1E and F) is in keeping with the presence of deeply characterized feedback loops in the case of HES1, where the amount of HES1 protein or its targets in the cell determine HES1 gene transcription rate (Kobayashi et al, 2009;Roese-Koerner et al, 2017;Duan et al, 2019). Similarly to HES1, which is expressed in cells and tissues in an oscillatory fashion (Kobayashi et al, 2009;Roese-Koerner et al, 2017), RASSF1A levels have also been described to oscillate through the cell cycle via degradation by SCF E3 ligase (Song et al, 2008) suggesting that these regulatory processes may be linked.…”

Downregulation of microRNA-29b by DNMT3B decelerates chondrocyte apoptosis and the progression of osteoarthritis via PTHLH/CDK4/RUNX2 axis

“…On the contrary, the addition of RUNX2 reversed the aforementioned regulatory effects of DNMT3B, indicating the positive role of RUNX2 in the modulation of ECM degradation. Consistently, the cell proliferation marker (Ki67) was suppressed by IL-1β treatment in the OA chondrocytes, indicating the inhibition of proliferation, and was further observed to be involved in the chondrogenic ECM degradation and OA progression [ 28 ]. Concordantly, the elevated expression of Aggrecan (a main cartilage matrix component) while reduced expression of MMP13 (a cartilage degrading enzyme) were reported in primary human OA chondrocytes after delivery of fibroblast growth factor receptor antagonists featured with promising beneficial action [ 29 ].…”

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

“…A disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTS) are key protease families involved in ECM remodeling; ADAMs modulate cell-ECM interactions and signal transduction through the cleavage of cell surface molecules, while ADAMTS specifically target ECM components such as proteoglycans and collagens, directly contributing to ECM structural changes and functional dynamics. For instance, ADAM8 indirectly contributes to the breakdown and restructuring of the ECM by regulating MMP9 expression, orchestrating the dynamic interplay between these crucial components in ECM remodeling [ 27 , 28 ]. Additionally, other tissue proteases, such as serine, aspartic, and cysteine proteases, also play significant roles in ECM remodeling [ 29 ].…”