Oleanolic acid, a small-molecule natural product, inhibits ECM degeneration in osteoarthritis by regulating the Hippo/YAP and Wnt/β-catenin pathways

Ma, Tianwen; Ruan, Hongri; Lv, Liangyu; Wei, Chengwei; Yu, Yue; Jia, Lina; Song, Xiaopeng; Zhang, Jiantao; Li, Yanan

doi:10.1039/d3fo01902k

Cited by 14 publications

(5 citation statements)

References 59 publications

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“…Induction of ferroptosis may increase MMPs protein expression and decrease collagen II expression in chondrocytes. 28,29 Overall, the above findings illustrate that silencing IGF2BP1 represses IL-1β-stimulated ferroptosis in primary chondrocytes by enhancing MMP3 mRNA stability. However, the shortcomings of the study are also need our attention and further study to solve the problem.…”

mentioning

confidence: 71%

IGF2BP1 Bolsters the Chondrocytes Ferroptosis of Osteoarthritis by Targeting m6A/MMP3 Axis

Zhao,

Dong,

Yang

et al. 2024

IJGM

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Chondrocyte degeneration and senescence are characteristics of osteoarthritis (OA) and other joint degenerative diseases, and ferroptosis has been observed to regulate the development of OA. However, the role of the N 6 -methyladenosine (m 6 A) modification in OA ferroptosis remains unclear. Methods: This study performed series of assays to investigate the function of the m 6 A reader IGF2BP1 in OA ferroptosis, including m 6 A quantitative analysis, Iron (Fe 2+ ) release analysis, Malondialdehyde (MDA) measurement, lipid peroxidation (ROS) detection and Glutathione (GSH) measurement. The molecular interaction and mechanism analysis was performed by Luciferase reporter assay, mRNA stability analysis and RNA immunoprecipitation (RIP) assay. Results: These results indicate that IGF2BP1 is upregulated in IL-1β-induced chondrocytes. Functionally, IGF2BP1 silencing represses ferroptosis, including iron (Fe 2+ ) accumulation, malondialdehyde, and reactive oxygen species (ROS). Mechanistically, among the potential downstream targets, matrix metalloproteinase-3 (MMP3) was observed to harbor a significant m 6 A modified site in the 3'-UTR. IGF2BP1 combines with MMP3 through the binding of m 6 A sites, thereby enhancing MMP3 mRNA stability. Discussion: In conclusion, our findings revealed the functions and mechanisms of m 6 A regulator IGF2BP1 in OA chondrocyte's ferroptosis, providing a novel target for OA treatment.

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mentioning

confidence: 71%

IGF2BP1 Bolsters the Chondrocytes Ferroptosis of Osteoarthritis by Targeting m6A/MMP3 Axis

Zhao,

Dong,

Yang

et al. 2024

IJGM

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“…In addition, with the process of abnormally differentiation and dedifferentiation, the significant enriched pathway for RegC-B was transformed into the Hippo signaling pathway. Most scholars believe that the Hippo-YAP signaling pathway plays a protective role against ( 29 , 30 ), but lack of reports on the role of the Hippo-TAZ pathway in the process of OA cartilage ( 31 ). The results of the current study suggest that Hippo-TAZ should be an important pathway to cause or against OA.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals different chondrocyte states in femoral cartilage between osteoarthritis and healthy individuals

Sun,

Yan,

Wang

et al. 2024

Front. Immunol.

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BackgroundCartilage injury is the main pathological manifestation of osteoarthritis (OA). Healthy chondrocyte is a prerequisite for cartilage regeneration and repair. Differences between healthy and OA chondrocyte types and the role these types play in cartilage regeneration and OA progression are unclear.MethodThis study conducted single-cell RNA sequencing (scRNA-seq) on the cartilage from normal distal femur of the knee (NC group) and OA femur (OA group) cartilage, the chondrocyte atlas was constructed, and the differences of cell subtypes between the two groups were compared. Pseudo-time and RNA velocity analysis were both performed to verify the possible differentiation sequence of cell subtypes. GO and KEGG pathway enrichment analysis were used to explore the potential functional characteristics of each cell subtype, and to predict the functional changes during cell differentiation. Differences in transcriptional regulation in subtypes were explored by single-cell regulatory network inference and clustering (SCENIC). The distribution of each cell subtype in cartilage tissue was identified by immunohistochemical staining (IHC).ResultA total of 75,104 cells were included, they were divided into 19 clusters and annotated as 11 chondrocyte subtypes, including two new chondrocyte subtypes: METRNL+ and PRG4+ subtype. METRNL+ is in an early stage during chondrocyte differentiation, and RegC-B is in an intermediate state before chondrocyte dedifferentiation. With cell differentiation, cell subtypes shift from genetic expression to extracellular matrix adhesion and collagen remodeling, and signal pathways shift from HIF-1 to Hippo. The 11 subtypes were finally classified as intrinsic chondrocytes, effector chondrocytes, abnormally differentiated chondrocytes and dedifferentiated chondrocytes. IHC was used to verify the presence and distribution of each chondrocyte subtype.ConclusionThis study screened two new chondrocyte subtypes, and a novel classification of each subtype was proposed. METRNL+ subtype is in an early stage during chondrocyte differentiation, and its transcriptomic characteristics and specific pathways provide a foundation for cartilage regeneration. EC-B, PRG4+ RegC-B, and FC are typical subtypes in the OA group, and the HippO-Taz pathway enriched by these cell subtypes may play a role in cartilage repair and OA progression. RegC-B is in the intermediate state before chondrocyte dedifferentiation, and its transcriptomic characteristics may provide a theoretical basis for intervening chondrocyte dedifferentiation.

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“…For example, Ma et al 112 reported that OA plays a protective role in joints mainly through promoting the secretion of collagen II and inhibiting the secretion of inflammatory cytokines such as IL-1β, TNF-α, MMP-3 and MMP-13. Mechanistically, this therapeutic effect depended on activating the Hippo/YAP pathway, which ultimately resulted in disruption of cartilage degradation.…”

Section: Atdc Cellsmentioning

confidence: 99%

“…Mechanistically, this therapeutic effect depended on activating the Hippo/YAP pathway, which ultimately resulted in disruption of cartilage degradation. 112 Resolvin D1 can modulate the YAP signaling pathway by promoting YAP phosphorylation in synovial cells, inhibiting the secretion of inflammatory factors and promoting the proliferation of aggressive synovial cells to delay the progression of cartilage degradation. 90 Aspirin also has therapeutic effects by mitigating the progression of cartilage degeneration by stabilizing YAP expression to reduce oxidative stress and inflammatory factor levels in vitro.…”

Section: Atdc Cellsmentioning

confidence: 99%

The Hippo-YAP Signaling Pathway in Osteoarthritis and Rheumatoid Arthritis

Li,

Zhang,

Bai

2024

JIR

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Arthritis is the most prevalent joint disease and is characterized by articular cartilage degradation, synovial inflammation, and changes in periarticular and subchondral bone. Recent studies have reported that Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) have significant effects on the proliferation, migration, and survival of chondrocytes and fibroblast-like synovial cells (FLSs). YAP/TAZ signaling pathway, as well as the related Hippo-YAP signaling pathway, are responsible for the condition of cells and articular cartilage in joints. They are tightly regulated to maintain metabolism in chondrocytes and FLSs because abnormal expression may result in cartilage damage. However, the roles and mechanisms of the Hippo-YAP pathway in arthritis remain largely unknown. This review summarizes the roles and key functions of YAP/TAZ and the Hippo-YAP signaling pathway in FLSs and chondrocytes for the induction of proliferation, migration, survival, and differentiation in rheumatoid arthritis (RA) and osteoarthritis (OA) research. We also discuss the therapeutic strategies involving YAP/TAZ and the related Hippo-YAP signaling pathway involved in OA.

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Oleanolic acid, a small-molecule natural product, inhibits ECM degeneration in osteoarthritis by regulating the Hippo/YAP and Wnt/β-catenin pathways

Abstract: Over the past few decades, osteoarthritis (OA) has been a major health problem worldwide. It is imminent to develop new, effective, and safe drugs to treat OA. There are many...

Cited by 14 publications

References 59 publications

IGF2BP1 Bolsters the Chondrocytes Ferroptosis of Osteoarthritis by Targeting m6A/MMP3 Axis

IGF2BP1 Bolsters the Chondrocytes Ferroptosis of Osteoarthritis by Targeting m6A/MMP3 Axis

Single-cell RNA sequencing reveals different chondrocyte states in femoral cartilage between osteoarthritis and healthy individuals

The Hippo-YAP Signaling Pathway in Osteoarthritis and Rheumatoid Arthritis

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