EGR1 promotes the cartilage degeneration and hypertrophy by activating the Krüppel-like factor 5 and β-catenin signaling

Sun, Xiaoning; Huang, Hai; Pan, Xuran; Li, Shuoda; Xie, Ziang; Ma, Yan; Hu, Bin; Wang, Jiying; Chen, Zhijun; Shi, Peihua

doi:10.1016/j.bbadis.2019.06.010

Cited by 50 publications

(34 citation statements)

References 28 publications

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“…In the adult, the mouse ENCODE transcriptome data set indicates that Egr1 is expressed in many if not all adult tissues, with high expression in cortex, mammary gland, ovary, and thymus [75]. In situ hybridization and immunohistochemistry experiments performed on adult mouse tissues show Egr1 expression in Achilles tendons [76], subcutaneous adipose tissue [77], hypertrophic cartilage [78,79], and bone [80,81].…”

Section: Egr1 Expression Profile In Vivomentioning

confidence: 99%

“…Bone is a supportive connective tissue composed of cells, fibers, and a mineralized solid ground substance [117]. Egr1 expression is detected in several areas undergoing endochondral bone formation, such as hypertrophic cartilage [78,79] and periostal regions of the developping long bones [72,73]. Egr1 is a negative regulator of cartilage markers [92].…”

Section: Egr1 and Endochondral Bone Formation And Healingmentioning

confidence: 99%

“…Chondrocytes stimulation with interleukin-1β (IL-1) leads to the recruitment of EGR1 to Pparg promoter and downregulates its expression, preventing the protective effect of PPARγ in osteoarthritis [96]. Ectopic expression of EGR1 in articular cartilage aggravated the degradation of the cartilage matrix in mice [78]. The excess of EGR1 induced an increase of transcripts and protein of type I collagen in synovial fibroblasts from rheumatoid arthritis patients [165].…”

Section: Egr1 and Matrix Production In Rheumatoid Arthritis And Osteomentioning

confidence: 99%

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EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

Havis

Duprez

2020

IJMS

398

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Although the transcription factor EGR1 is known as NGF1-A, TIS8, Krox24, zif/268, and ZENK, it still has many fewer names than biological functions. A broad range of signals induce Egr1 gene expression via numerous regulatory elements identified in the Egr1 promoter. EGR1 is also the target of multiple post-translational modifications, which modulate EGR1 transcriptional activity. Despite the myriad regulators of Egr1 transcription and translation, and the numerous biological functions identified for EGR1, the literature reveals a recurring theme of EGR1 transcriptional activity in connective tissues, regulating genes related to the extracellular matrix. Egr1 is expressed in different connective tissues, such as tendon (a dense connective tissue), cartilage and bone (supportive connective tissues), and adipose tissue (a loose connective tissue). Egr1 is involved in the development, homeostasis, and healing processes of these tissues, mainly via the regulation of extracellular matrix. In addition, Egr1 is often involved in the abnormal production of extracellular matrix in fibrotic conditions, and Egr1 deletion is seen as a target for therapeutic strategies to fight fibrotic conditions. This generic EGR1 function in matrix regulation has little-explored implications but is potentially important for tendon repair.

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Section: Egr1 Expression Profile In Vivomentioning

confidence: 99%

Section: Egr1 and Endochondral Bone Formation And Healingmentioning

confidence: 99%

Section: Egr1 and Matrix Production In Rheumatoid Arthritis And Osteomentioning

confidence: 99%

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EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

Havis

Duprez

2020

IJMS

398

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“…1550008-55-3, US). All the mice were treated with ML246 (15 mg/kg) or the vehicle solution as the negative control, as previously described [59]. All the mice were injected intraperitoneally every two days for 14 or 28 days.…”

Section: Animal Studymentioning

confidence: 99%

Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission

Zheng

Liu

et al. 2020

PLoS Biol

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Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krü ppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.

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“…In addition, hypoxia directly regulates the secretion of vascular endothelial growth factor (VEGF) and inflammatory cytokines such as interleukin (IL)-6 (Arjamaa et al, 2017). These i n fl a m m a t o r y m e d i a t o r s c a n u p r e g u l a t e m a t r i x metalloproteinase (MMP) expression and decrease tissue inhibitor of metalloproteinase (TIMP) production, resulting in degradation of the extracellular matrix and chondrocyte apoptosis (Ying et al, 2017;Sun et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Low-Intensity Pulsed Ultrasound Alleviates Hypoxia-Induced Chondrocyte Damage in Temporomandibular Disorders by Modulating the Hypoxia-Inducible Factor Pathway

et al. 2020

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Temporomandibular disorders are a common cause of chronic pain in the orofacial region and have a complex and multi-factorial pathophysiology. Mechanical loading or inflammatory conditions have been shown to decrease oxygen tension within the joint cartilage and activate the hypoxia-inducible factor (HIF) pathway, which in turn aggravates the pathological processes underlying temporomandibular joint (TMJ) disorders. We previously showed that low-intensity pulsed ultrasound (LIPUS) treatment effectively repairs TMJ injury induced by chronic sleep deprivation (CSD). Here, we explored the effects of LIPUS treatment on hypoxia-induced chondrocyte injury. We found that it effectively restored the proliferation capacity of mandibular chondrocytes under hypoxic conditions and lowered their rate of apoptosis. Chondrogenic capacity, as assessed by type II collagen levels, and mucin-positive areas were also significantly increased after LIPUS treatment. Levels of matrix metalloprotein-3 and interleukin-6 decreased in mandibular chondrocytes following this treatment, whereas the expression of tissue inhibitor of metalloproteinase-1 increased. We also found that HIF-1a expression was upregulated in mandibular chondrocytes under hypoxic conditions and was further enhanced by LIPUS treatment. Similarly, HIF-2a levels increased in mandibular chondrocytes under hypoxic conditions but decreased following LIPUS treatment. Subsequently, we established a CSD-induced TMJ injury model and found that LIPUS increased mucin-positive areas as well as HIF-1a expression and decreased HIF-2 level in the chondrocyte layer. Together, our results indicate that the protective effect of LIPUS on chondrocyte is partly associated with the HIF pathway.

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EGR1 promotes the cartilage degeneration and hypertrophy by activating the Krüppel-like factor 5 and β-catenin signaling

Cited by 50 publications

References 28 publications

EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission

Low-Intensity Pulsed Ultrasound Alleviates Hypoxia-Induced Chondrocyte Damage in Temporomandibular Disorders by Modulating the Hypoxia-Inducible Factor Pathway

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