Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis

Fisch, Kathleen M.; Gamini, Ramya; Álvarez-García, Óscar; Akagi, Ryuichiro; Saito, M.; Muramatsu, Yusuke; Sasho, Takahisa; Koziol, James A.; Su, Andrew I.; Lotz, Martin

doi:10.1016/j.joca.2018.07.012

Cited by 176 publications

(189 citation statements)

References 62 publications

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“…Other predicted ECM genes bound by FoxO1 ( COL3A1 , COL5A2 ) and nonbound genes ( COL1A1 ) remained unchanged after AS1842856 treatment. We also observed a significant inhibition of RORC and NR1D1 , core clock circadian genes that are dysregulated in OA (). PER1 is also a core clock circadian gene dysregulated in OA, but no significant effect was observed upon treatment with AS1842856.…”

Section: Resultsmentioning

confidence: 67%

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Genome‐Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes

Duffy

Bekki

Lotz

2020

Arthritis & Rheumatology

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Objective Osteoarthritis (OA) is the most common age‐related joint disease. With aging and in OA, the expression of FoxO transcription factors is reduced, diminishing their chondroprotective actions. In order to elucidate the molecular mechanisms by which FoxO1 protects chondrocytes, we sought to identify the genome‐wide occupancy profile of FoxO1. Methods We performed FoxO1 chromatin immunoprecipitation followed by high‐throughput sequencing (ChIP‐Seq) on human primary chondrocytes. ChIP‐Seq data were integrated with RNA sequencing (RNA‐Seq) data sets. Bioinformatics results were confirmed in primary chondrocytes that were treated with a FoxO1 inhibitor. Results Analysis of FoxO1 ChIP‐Seq on human primary chondrocytes showed that pathways implicated in OA pathogenesis are mainly regulated by FoxO1 binding to tissue‐specific enhancers with suboptimal binding sites (20% of the peaks), while more ubiquitous FoxO1 pathways are regulated at the promoter level through interaction with its canonical binding motif (7% of the peaks). Integrating FoxO1 occupancy data with RNA‐Seq data comparing OA and healthy human cartilage revealed 428 putative FoxO1 target genes that are dysregulated in OA. Pathway analysis showed enrichment for genes belonging to the senescence pathway (logP = −6.73), extracellular matrix (ECM) pathway (logP = −12.97), and circadian clock pathway (logP = −6.30), which suggests that FoxO1 dysregulation plays an important role in their abnormal expression in OA. Using an inhibitor of FoxO1, we confirmed that FoxO1 regulates these pathways in cultured human chondrocytes. Conclusion FoxO1 regulates ubiquitous and cartilage‐specific genes in chondrocytes by using different mechanisms. The FoxO1 transcriptional network is a key player in regulating homeostasis, ECM, and circadian clock genes and plays an important role in the abnormal expression of these pathways observed in OA pathogenesis.

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Section: Resultsmentioning

confidence: 67%

“…Previous findings from our group and others have shown that the circadian clock is disrupted in human OA () and that perturbation of the circadian clock promotes OA pathogenesis (). Furthermore, FoxO pathways are disrupted in OA (1) and have been linked to circadian rhythms ().…”

Section: Discussionmentioning

confidence: 75%

Genome‐Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes

Duffy

Bekki

Lotz

2020

Arthritis & Rheumatology

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“…To frame the power of EV-miRNAs in the OA setting, the 818 target mRNAs were filtered through 2368 abundantly expressed genes, identified as laying in the first quartile of expression (out of 9474 total genes), in cartilage biopsies from OA patients [44]. After filtering, 224 EV-miRNA targets were left and shared ( Supplementary Table S3).…”

Section: Target and Effect Prediction Of Ev-mirnas On Oa-cartilagementioning

confidence: 99%

Secreted Factors and EV-miRNAs Orchestrate the Healing Capacity of Adipose Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis

Ragni

Orfei

Luca

et al. 2020

IJMS

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Mesenchymal stem cells (MSCs) derived from adipose tissue and used either as expanded cells or minimally manipulated cell preparations showed positive clinical outcomes in regenerative medicine approaches based on tissue restoration and inflammation control, like in osteoarthritis (OA). Recently, MSCs’ healing capacity has been ascribed to the large array of soluble factors, including soluble cytokines/chemokines and miRNAs conveyed within extracellular vesicles (EVs). Therefore, in this study, 200 secreted cytokines, chemokines and growth factors via ELISA, together with EV-embedded miRNAs via high-throughput techniques, were scored in adipose-derived MSCs (ASCs) cultivated under inflammatory conditions, mimicking OA synovial fluid. Both factors (through most abundantly expressed TIMP1, TIMP2, PLG and CTSS) and miRNAs (miR-24-3p, miR-222-3p and miR-193b-3p) suggested a strong capacity for ASCs to reduce matrix degradation activities, as those activated in OA cartilage, and switch synovial macrophages, often characterized by an M1 inflammatory polarization, towards an M2 phenotype. Moreover, the crucial importance of selecting the target tissue is discussed, showing how a focused search may greatly improve potency prediction and explain clinical outcomes. In conclusion, herein presented data shed light about the way ASCs regulate cell homeostasis and regenerative pathways in an OA-resembling environment, therefore suggesting a rationale for the use of MSC-enriched clinical products, such as stromal vascular fraction and microfragmented adipose tissue, in joint pathologies.

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“…To evaluate the general expression profile of genes in OA, previously published gene expression datasets were analyzed by array and high throughput sequencing. The gene expression data of GSE114007 (32) and GSE117999 (33) were downloaded from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo). GSE114007 compared the genome-wide molecular profile of 20 patients with OA and 18 controls based on the GPL11154 (Illumina HiSeq 2000) and GPL18573 (Illumina NextSeq 500) platforms.…”

Section: Collection Of Serum Samples From Patients the Involvement Omentioning

confidence: 99%

Circulating microRNA let‑7e is decreased in knee osteoarthritis, accompanied by elevated apoptosis and reduced autophagy

Feng

Wang

et al. 2020

Int J Mol Med

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Knee osteoarthritis (KOA) is a major cause of leg disability in the elderly population. Recently, the expression levels of circulating microRNA (miRNA) let-7e have been reported to be significantly reduced in KOA. The aims of the present study were to assess the feasibility of let-7e as a serum marker for detecting KOA and to explore the underlying mechanisms of its involvement. Based on previous studies and bioinformatics analysis, let-7e may regulate apoptosis and autophagy of articular chondrocytes. A total of 10 patients with KOA and 10 patients with trauma without KOA were recruited to examine the levels of let-7e in peripheral blood. Subsequently, KOA rat models were established, and the levels of let-7e in the cartilage and serum were examined, the expression of apoptotic proteins and autophagy-related proteins in the cartilage were investigated, and apoptotic and autophagic activities of primary cultured chondrocytes were also detected. In patients with KOA, let-7e levels in the peripheral serum were significantly decreased compared with the control group, and this result was confirmed in the peripheral serum and cartilage of KOA rats. In addition, the expression levels of proteins involved in the apoptotic pathway were increased in the cartilage of KOA rats, and apoptotic activity was increased. The expression of autophagy-related proteins beclin 1 and microtubule associated protein 1 light chain 3 β (Lc3B) II/Lc3BI in the articular cartilage of KOA rats was lower compared with the controls, and autophagy was decreased. Si-Miao-San (SMS) treatment restored the expression of let-7e and reversed the changes in apoptosis and autophagy. Therefore, the present study provided additional evidence that circulating let-7e may be a potential serum biomarker for the diagnosis and treatment of KOA. Elevated apoptosis levels and decreased autophagy levels of cartilage tissue are involved in KOA, and treatment with SMS may reverse these effects.

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Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis

Abstract: We identified a novel subnetwork of dysregulated TFs that represent new mediators of abnormal gene expression and promising therapeutic targets in OA.

Cited by 176 publications

References 62 publications

Genome‐Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes

Genome‐Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes

Secreted Factors and EV-miRNAs Orchestrate the Healing Capacity of Adipose Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis

Circulating microRNA let‑7e is decreased in knee osteoarthritis, accompanied by elevated apoptosis and reduced autophagy

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