De novo serine synthesis regulates chondrocyte proliferation during bone development and repair

Stegen, Steve; Loopmans, Shauni; Stockmans, Ingrid; Moermans, Karen; Carmeliet, Peter; Carmeliet, Geert

doi:10.1038/s41413-021-00185-7

Cited by 21 publications

(13 citation statements)

References 45 publications

(96 reference statements)

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“…Ammonia treatment led to an increase in LC3b and p62, likely through blockade of autophageosome-lysosome fusion. We also observe that glutamate supplementation appeared to increase autophagy, as noted by a decrease in p62 levels (Fig 4D One of the major cell stress response factors involved in regulating metabolism and autophagy is Activating transcription factor 4 (ATF4), which can modulate intracellular metabolism (B'Chir et al, 2013;O'Leary et al, 2020;Stegen et al, 2022). Mechanistically, we observe that glutamine deprivation is able to increase ATF4 protein expression, which is reduced with IL-1β stimulation (Figure 4 Supplement 4H-I).…”

Section: Glutamine Deprivation Activates Autophagymentioning

confidence: 73%

“…One of the major cell stress response factors involved in regulating metabolism and autophagy is Activating transcription factor 4 (ATF4), which can modulate intracellular metabolism(B’Chir et al, 2013; O’Leary et al, 2020; Stegen et al, 2022). Mechanistically, we observe that glutamine deprivation is able to increase ATF4 protein expression, which is reduced with IL-1β stimulation (Figure 4 Supplement 4H-I).…”

Section: Resultsmentioning

confidence: 99%

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Glutamine metabolism modulates chondrocyte inflammatory response

Arra¹,

Swarnkar²,

Adapala³

et al. 2022

Preprint

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Osteoarthritis is the most common joint disease in the world with significant societal consequences, but lacks effective disease modifying interventions. The pathophysiology consists of a prominent inflammatory component that can be targeted to prevent cartilage degradation and structural defects. Intracellular metabolism has emerged as a culprit of the inflammatory response in chondrocytes, with both processes co-regulating each other. The role of glutamine metabolism in chondrocytes, especially in the context of inflammation, lacks a thorough understanding and is the focus of this work. We display that chondrocytes utilize glutamine for energy production and anabolic processes. Furthermore, we show that glutamine deprivation itself causes metabolic reprogramming and decreases the inflammatory response of chondrocytes through inhibition of NF-κB activity. Finally, we display that glutamine deprivation promotes autophagy and that ammonia is an inhibitor of autophagy. Overall, we identify a relationship between glutamine metabolism and inflammatory signaling and display the need for increased study of chondrocyte metabolic systems.

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Section: Glutamine Deprivation Activates Autophagymentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Glutamine metabolism modulates chondrocyte inflammatory response

Arra¹,

Swarnkar²,

Adapala³

et al. 2022

Preprint

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show abstract

“…One of the major cell stress response factors involved in regulating metabolism and autophagy is activating transcription factor 4 (ATF4), which can modulate intracellular metabolism ( B’chir et al, 2013 ; O’Leary et al, 2020 ; Stegen et al, 2022 ). Mechanistically, we observe that glutamine deprivation is able to increase ATF4 protein expression, which is reduced with IL-1β stimulation ( Figure 4—figure supplement 1N-O ).…”

Section: Resultsmentioning

confidence: 99%

Glutamine metabolism modulates chondrocyte inflammatory response

Arra¹,

Swarnkar²,

Adapala³

et al. 2022

eLife

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Osteoarthritis is the most common joint disease in the world with significant societal consequences, but lacks effective disease modifying interventions. The pathophysiology consists of a prominent inflammatory component that can be targeted to prevent cartilage degradation and structural defects. Intracellular metabolism has emerged as a culprit of the inflammatory response in chondrocytes, with both processes co-regulating each other. The role of glutamine metabolism in chondrocytes, especially in the context of inflammation, lacks a thorough understanding and is the focus of this work. We display that mouse chondrocytes utilize glutamine for energy production and anabolic processes. Furthermore, we show that glutamine deprivation itself causes metabolic reprogramming and decreases the inflammatory response of chondrocytes through inhibition of NF-κB activity. Finally, we display that glutamine deprivation promotes autophagy and that ammonia is an inhibitor of autophagy. Overall, we identify a relationship between glutamine metabolism and inflammatory signaling and display the need for increased study of chondrocyte metabolic systems.

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“…Over time, these hypertrophic chondrocytes are gradually replaced by bone ( Wuelling and Vortkamp 2010 ). Disruption of the G1/S checkpoint is a critical step in chondrocyte proliferation and skeletal growth ( Stegen et al . 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Kmt2d leads to growth impairment by activating the Akt/β-catenin signaling pathway

Shangguan,

Huang,

Lin

et al. 2024

G3: Genes, Genomes, Genetics

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The KMT2D variant–caused Kabuki syndrome (KS) is characterized by short stature as a prominent clinical characteristic. The initiation and progression of body growth are fundamentally influenced by chondrocyte proliferation. Uncertainty persists regarding the possibility that KMT2D deficiency affects growth by impairing chondrocyte proliferation. In this study, we used the CRISPR/Cas13d technique to knockdown kmt2d in zebrafish embryos and lentivirus to create a stable Kmt2d gene knockdown cell line in chondrocytes (ATDC5 cells). We also used CCK8 and flow cytometric studies, respectively, to determine proliferation and cell cycle state. The relative concentrations of phosphorylated Akt (ser473), phosphorylated β-catenin (ser552), and cyclin D1 proteins in chondrocytes and zebrafish embryos were determined by using western blots. In addition, Akt inhibition was used to rescue the phenotypes caused by kmt2d deficiency in chondrocytes, as well as a zebrafish model that was generated. The results showed that a knockdown of kmt2d significantly decreased body length and resulted in aberrant cartilage development in zebrafish embryos. Furthermore, the knockdown of Kmt2d in ATDC5 cells markedly increased proliferation and accelerated the G1/S transition. In addition, the knockdown of Kmt2d resulted in the activation of the Akt/β-catenin signaling pathway in ATDC5 cells. Finally, Akt inhibition could partly rescue body length and chondrocyte development in the zebrafish model. Our study demonstrated that KMT2D modulates bone growth conceivably via regulation of the Akt/β-catenin pathway.

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De novo serine synthesis regulates chondrocyte proliferation during bone development and repair

Cited by 21 publications

References 45 publications

Glutamine metabolism modulates chondrocyte inflammatory response

Glutamine metabolism modulates chondrocyte inflammatory response

Glutamine metabolism modulates chondrocyte inflammatory response

Knockdown of Kmt2d leads to growth impairment by activating the Akt/β-catenin signaling pathway

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