GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression DOI Creative Commons
Kai Shen, Hao Zhou, Qiang Zuo

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Dec. 30, 2024

Accumulating evidence indicates that cellular senescence is closely associated with osteoarthritis. However, there limited research on the mechanisms underlying fibroblast-like synoviocyte and its impact osteoarthritis progression. Here, we elucidate a positive correlation between progression reveal GATD3A deficiency induces senescence. Mechanistically, enhances binding of Sirt3 to MDH2, leading deacetylation decreased activity MDH2. Reduced MDH2 impairs tricarboxylic acid cycle flux, resulting in mitochondrial dysfunction Intra-articular injection recombinant adeno-associated virus carrying significantly alleviates phenotype male mice. This study increases our current understanding function. In particular, novel mechanism senescence, suggesting targeting potential therapeutic approach for The are unclear. authors show mice demonstrate symptoms mouse models

Language: Английский

Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: a narrative review DOI Creative Commons
Jana Riegger, Astrid Schoppa,

Leonie Ruths

et al.

Cellular & Molecular Biology Letters, Journal Year: 2023, Volume and Issue: 28(1)

Published: Sept. 30, 2023

Abstract During aging and after traumatic injuries, cartilage bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS), damage-associated molecular patterns, proinflammatory cytokines. This detrimental environment triggers cellular stress subsequent dysfunction, which not only contributes the development of associated diseases, that is, osteoporosis osteoarthritis, but also impairs regenerative processes. To counter ROS-mediated reduce overall tissue damage, possess diverse defense mechanisms. However, antioxidative capacities limited thus ROS accumulation can lead aberrant cell fate decisions, have adverse effects on homeostasis. In this narrative review, we address oxidative as a major driver processes in bone, senescence, misdirected differentiation, death, mitochondrial impaired mitophagy by illustrating consequences homeostasis regeneration. Moreover, elaborate mechanisms, with particular focus response mitophagy, briefly discuss respective therapeutic strategies improve protection.

Language: Английский

Citations

78
The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF‐1α to inhibit knee osteoarthritis‐induced ferroptosis DOI Creative Commons
Zhiyuan Guan, Xiao Jin, Zhiqiang Guan

et al.

Aging Cell, Journal Year: 2023, Volume and Issue: 22(6)

Published: March 8, 2023

Abstract Ferroptosis is an iron‐dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota‐ OA axis refers bidirectional information network between microbiota OA, which may provide a new way protect OA. However, role microbiota‐derived metabolites in ferroptosis‐relative remains unclear. The objective this study was analyze protective effect its metabolite capsiate (CAT) on vivo vitro experiments. From June 2021 February 2022, 78 patients were evaluated retrospectively divided into two groups: health group ( n = 39) 40). Iron oxidative stress indicators determined peripheral blood samples. And then experiments, surgically destabilized medial meniscus (DMM) mice model established treated with CAT or Ferric Inhibitor‐1 (Fer‐1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) utilized inhibit SLC2A1 expression. Serum iron increased significantly but total binding capacity decreased than healthy people p < 0.0001). least absolute shrinkage selection operator clinical prediction suggested serum iron, capacity, transferrin, superoxide dismutase all independent predictors 0.001). Bioinformatics results SLC2A1, Metastasis‐Associated Lung Adenocarcinoma Transcript (MALAT1), HIF‐1α (Hypoxia Inducible Factor Alpha)‐related signaling pathways play important homeostasis In addition, 16s sequencing untargeted metabolomics used find negatively correlated Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration 0.0017). Moreover, reduced ferroptosis‐dependent vitro. against could be eliminated by silencing SLC2A1. upregulated levels DMM group. HIF‐1α, MALAT1, apoptosis after knockout chondrocyte cells Finally, downregulation expression Adeno‐associated Virus (AAV) ‐SLC2A1 shRNA improves vivo. Our findings indicated inhibited HIF‐1a activating

Language: Английский

Citations

61
Nutrition Strategies Promoting Healthy Aging: From Improvement of Cardiovascular and Brain Health to Prevention of Age-Associated Diseases DOI Open Access
Mónika Fekete, Z Szarvas, Vince Fazekas‐Pongor

et al.

Nutrients, Journal Year: 2022, Volume and Issue: 15(1), P. 47 - 47

Published: Dec. 22, 2022

An increasing number of studies suggest that diet plays an important role in regulating aging processes and modulates the development most age-related diseases.The aim this review is to provide overview relationship between nutrition critical age-associated diseases.A literature was conducted survey recent pre-clinical clinical findings related nutritional factors modulation fundamental cellular molecular mechanisms their prevention genesis diseases aging.Studies show cardiovascular cerebrovascular diseases, neurodegenerative cognitive impairment dementia can be slowed down or prevented by certain diets with anti-aging action. The protective effects diets, at least part, may mediated beneficial macro- (protein, fat, carbohydrate) micronutrient (vitamins, minerals) composition.Certain such as Mediterranean diet, play a significant healthy preventing onset improving process itself. This latter strengthened incorporating fasting elements into diet. As dietary recommendations change age, should taken consideration well, when developing tailored needs elderly individuals. Future ongoing on complex interventions translating results preclinical investigations are expected lead novel guidelines for older adults near future.

Language: Английский

Citations

64
Osteoarthritis year in review 2023: Biology DOI Creative Commons
Anke J. Roelofs, Cosimo De Bari

Osteoarthritis and Cartilage, Journal Year: 2023, Volume and Issue: 32(2), P. 148 - 158

Published: Nov. 7, 2023

Great progress continues to be made in our understanding of the multiple facets osteoarthritis (OA) biology. Here, we review major advances this field and towards therapy development over past year, highlighting a selection relevant published literature from PubMed search covering year end April 2022 2023. The selected articles have been arranged themes. These include 1) molecular regulation articular cartilage implications for OA, 2) mechanisms subchondral bone remodelling, 3) role synovium inflammation, 4) age-related changes including matrix stiffening, cellular senescence, mitochondrial dysfunction, metabolic impaired autophagy, 5) peripheral OA pain. Progress responsible aspects biology is unravelling novel therapeutic targets disease modification.

Language: Английский

Citations

32
Aging and the emerging role of cellular senescence in osteoarthritis DOI
Brian O. Diekman, Richard F. Loeser

Osteoarthritis and Cartilage, Journal Year: 2023, Volume and Issue: 32(4), P. 365 - 371

Published: Dec. 2, 2023

Language: Английский

Citations

25
N6-methyladenosine hypomethylation of circGPATCH2L regulates DNA damage and apoptosis through TRIM28 in intervertebral disc degeneration DOI
Zhenhao Chen, Jian Song, Lin Xie

et al.

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(8), P. 1957 - 1972

Published: July 12, 2023

Language: Английский

Citations

23
Comet assay for quantification of the increased DNA damage burden in primary human chondrocytes with aging and osteoarthritis DOI Creative Commons
Michaela E. Copp, S. Chubinskaya, Daniel N. Bracey

et al.

Aging Cell, Journal Year: 2022, Volume and Issue: 21(9)

Published: Aug. 22, 2022

It is known that chondrocytes from joints with osteoarthritis (OA) exhibit high levels of DNA damage, but the degree to which accumulate damage during "normal aging" has not been established. The goal this study was quantify present in obtained cadaveric donors a wide age range, and compare extent OA chondrocytes. alkaline comet assay used measure normal cartilage ankle (talus) knee (femur) donors, as well at time total replacement. Chondrocytes younger (<45 years) had less than older (>70 assessed by percentage "tail". In between 50 60 years old, there increased compared cadaveric. Talar 23 ages 34 78 revealed linear increase (R2 = 0.865, p < 0.0001). A "two-tailed" demonstrate most accumulated form strand breaks opposed alkali-labile base damage. young required 10 Gy irradiation recapitulate donors. Given potential for contribute chondrocyte dysfunction senescence, supports investigation mechanisms hypo-replicative cell types

Language: Английский

Citations

27
Sirt6 promotes DNA damage repair in osteoarthritis chondrocytes by activating the Keap1/Nrf2/HO-1 signaling pathway DOI

Lingwei Mao,

Qin-Yi Jiang,

Nan Meng

et al.

Cell Cycle, Journal Year: 2024, Volume and Issue: 23(2), P. 205 - 217

Published: Jan. 17, 2024

The aim of this study was to explore the effect and mechanism Sirt6 on DNA damage repair in OA chondrocytes. Cartilage tissues were collected from patients with knee arthroplasty traumatic amputation without OA. Besides, 7-week-old male C57BL/6 mice randomly divided into Control groups; CHON-001 cells corresponding groups treated 10 ng/ml interleukin (IL)-1β, respectively. Subsequently, or siNrf2 over-expressed observe senescence chondrocytes by IL-1β through nuclear factor E2-related 2 (Nrf2) signaling pathway. expression level human mouse cartilage significantly decreased. However, 24 h treatment decreased chondrocytes, induced damage, promoted cellular senescence. In addition, over-expression inhibited IL-1β-induced Moreover, overexpression activated Keap1/Nrf2/HO-1 pathway while knockdown Nrf2 anti-senescence effects IL-1β-treated may reduce activating

Language: Английский

Citations

5
In vitro study to identify ligand‐independent function of estrogen receptor‐α in suppressing DNA damage‐induced chondrocyte senescence DOI Creative Commons
Xiurui Zhang,

Shiqi Xiang,

Yiqian Zhang

et al.

The FASEB Journal, Journal Year: 2023, Volume and Issue: 37(2)

Published: Jan. 9, 2023

Abstract In osteoarthritis (OA), chondrocytes undergo many pathological alternations that are linked with cellular senescence. However, the exact pathways lead to generation of a senescence‐like phenotype in OA not clear. Previously, we found loss estrogen receptor‐α (ERα) was associated an increased senescence level human chondrocytes. Since DNA damage is common cause senescence, aimed study relationship among ERα levels, damage, and We first examined levels ERα, representative markers normal cartilage harvested from male female donors, as well mice. The influence on studied by treating doxorubicin (DOX), which often‐used DNA‐damaging agent. Next, tested potential overexpressing reducing levels. Lastly, explored interaction between nuclear factor kappa‐light‐chain‐enhancer activated B cells (NF‐κB) pathway. Results indicated contained displayed features, were accompanied significantly reduced Overexpression DOX‐treated Moreover, DOX‐induced activation NF‐κB pathway, partially reversed ERα. Taken together, our results demonstrated critical role maintaining health inhibiting This also suggests may represent new avenue prevent treat OA.

Language: Английский

Citations

11
An inducible long noncoding RNA, LncZFHX2, facilitates DNA repair to mediate osteoarthritis pathology DOI Creative Commons
Weiyu Ni, Haitao Zhang,

Zixuan Mei

et al.

Redox Biology, Journal Year: 2023, Volume and Issue: 66, P. 102858 - 102858

Published: Aug. 19, 2023

Cartilage homeostasis is essential for chondrocytes to maintain proper phenotype and metabolism. Because adult articular cartilage avascular, must survive in low oxygen conditions, changing tension can significantly affect metabolism proteoglycan synthesis these cells. However, whether long noncoding RNA participate under hypoxia has not been reported yet. Here, we first identified LncZFHX2 as a lncRNA upregulated physiological cartilage, specifically by HIF-1α. knockdown simultaneously accelerated cellular senescence, targeted multiple components of extracellular matrix metabolism, increased DNA damage chondrocytes. Through series vitro vivo experiments, that performed novel function regulated RIF1 expression through forming transcription complex with KLF4 promoting chondrocyte repair. Moreover, chondrocyte-conditional knockout injury-induced degeneration vivo. In conclusion, hypoxia-activated repair pathway maintains osteoarthritis cartilage.

Language: Английский

Citations

11