GO:0090272 negative regulation of fibroblast growth factor production: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0090272 describes any process that decreases the rate, frequency or extent of fibroblast growth factor (FGF) appearance due to biosynthesis or secretion following a cellular stimulus.
• FGF23 production is suppressed by insulin signaling, establishing a direct endocrine link between metabolic status and FGF23 levels.
• Inflammation is a key regulator of FGF23 production, with pro-inflammatory cytokines increasing FGF23 while anti-inflammatory signals may suppress it.
• FGF21 is an endocrine inhibitor of sugar and alcohol appetite, and its production is subject to negative regulation in metabolic contexts.
• Autophagy and MTORC2 signaling drive fibroblast senescence and influence FGF production in tissue remodeling.
• CRISPR knockout, knock-in, and overexpression models are essential for dissecting the causal roles of genes that negatively regulate FGF production.
Description
The Gene Ontology term GO:0090272, negative regulation of fibroblast growth factor production, defines any process that decreases the rate, frequency or extent of the appearance of a fibroblast growth factor (FGF) due to biosynthesis or secretion following a cellular stimulus, resulting in an increase in its intracellular or extracellular levels. FGFs are a family of signaling proteins with critical roles in development, metabolism, and tissue repair, and their production must be tightly controlled to maintain physiological homeostasis. Dysregulated FGF production is associated with a range of pathological conditions, including chronic kidney disease, heart failure with preserved ejection fraction, and metabolic disorders. Understanding the mechanisms that negatively regulate FGF production is therefore of significant biomedical interest. This article synthesizes authoritative QuickGO data and verified PubMed literature to provide a research-grade overview of GO:0090272, covering its definition, biological significance, key genes, regulatory mechanisms, disease associations, and experimental approaches for investigation. Researchers studying this process can leverage CRISPR-based models to dissect the causal roles of specific genes in FGF production and to identify novel therapeutic targets.
negative regulation of fibroblast growth factor production At A Glance
| GO ID | GO:0090272 |
|---|---|
| GO term | negative regulation of fibroblast growth factor production |
| Ontology | biological_process |
| Synonym | none |
| Definition | Any process that decreases the rate, frequency or extent of the appearance of a fibroblast growth factor due to biosynthesis or secretion following a cellular stimulus, resulting in an increase in its intracellular or extracellular levels. |
| Major function | Suppression of FGF biosynthesis or secretion to modulate endocrine and paracrine signaling. |
| Related processes | Insulin signaling, inflammatory response, autophagy, MTORC2 signaling, ROS-responsive pathways. |
| Key FGFs | FGF23, FGF21, FGF2, FGF10, FGF18. |
| Disease relevance | Chronic kidney disease, heart failure with preserved ejection fraction, metabolic disorders, fibrosis. |
What Is GO:0090272?
GO:0090272 is a biological process term that encompasses any cellular or molecular mechanism that reduces the biosynthesis or secretion of a fibroblast growth factor in response to a stimulus. This negative regulation can occur at multiple levels, including transcriptional repression, mRNA stability, translational inhibition, or blockade of secretion. The term specifically refers to a decrease in the rate, frequency, or extent of FGF appearance, leading to lower intracellular or extracellular FGF levels. It is distinct from positive regulation of FGF production and from general regulation of growth factor signaling. The definition is based on the QuickGO annotation for GO:0090272 and is supported by experimental evidence from studies on FGF23 and FGF21 regulation.
Why Is negative regulation of fibroblast growth factor production Important in Cell Biology?
Negative regulation of fibroblast growth factor production is critically important because FGFs are potent signaling molecules that influence diverse physiological processes, including phosphate and vitamin D metabolism, energy homeostasis, cardiac function, and tissue repair. Excessive or inappropriate FGF production contributes to the pathogenesis of several diseases, such as chronic kidney disease with hyperphosphatemia, heart failure with preserved ejection fraction, and metabolic syndrome. Conversely, insufficient negative regulation can lead to fibrosis and aberrant tissue remodeling. Understanding the molecular mechanisms that suppress FGF production provides opportunities for therapeutic intervention. For example, insulin-mediated suppression of FGF23 production highlights a direct link between metabolic status and endocrine FGF regulation. Inflammatory signals also modulate FGF23, suggesting that targeting inflammation could influence FGF23 levels in disease. Moreover, FGF21, an endocrine inhibitor of sugar and alcohol appetite, is subject to negative regulation that impacts metabolic health. Thus, GO:0090272 is a nexus for metabolic, inflammatory, and cardiovascular research.
• Regulates phosphate and vitamin D homeostasis through FGF23 suppression.
• Links insulin signaling to endocrine FGF production, impacting metabolic health.
• Modulates inflammatory responses that drive FGF23 production in chronic kidney disease.
• Influences cardiac mitochondrial bioenergetics and heart failure outcomes via FGF21.
• Controls fibroblast senescence and tissue remodeling through autophagy and MTORC2.
• Impacts wound healing by regulating keratinocyte and fibroblast activation.
• Provides therapeutic targets for idiopathic pulmonary fibrosis via ROS-responsive pathways.
• Affects appetite regulation and alcohol consumption through FGF21.
• Serves as a model for studying endocrine FGF regulation in aging and thymic involution.
• Enables CRISPR-based dissection of causal genes in FGF-related diseases.
What Happens During negative regulation of fibroblast growth factor production?
Stimulus sensing and signal transduction
In simple terms: Cells first detect external or internal signals that tell them to reduce FGF production.
Negative regulation of FGF production begins with the sensing of stimuli such as insulin, inflammatory cytokines, or metabolic stress. Insulin signaling is a well-characterized negative regulator of FGF23 production, where insulin receptor activation leads to downstream suppression of FGF23 gene expression. Inflammatory signals, particularly pro-inflammatory cytokines, can either stimulate or suppress FGF23 depending on context, but anti-inflammatory pathways may contribute to negative regulation. Reactive oxygen species (ROS) can also modulate FGF production through Nrf2 signaling, as shown in idiopathic pulmonary fibrosis models. These stimuli activate intracellular signaling cascades that ultimately converge on transcriptional or post-transcriptional control of FGF genes.
Transcriptional suppression of FGF genes
In simple terms: The cell reduces the reading of FGF genes into mRNA.
Once signals are transduced, transcription factors and co-regulators are recruited to FGF gene promoters to suppress transcription. For FGF23, insulin signaling has been shown to suppress its production at the transcriptional level. In the context of inflammation, NF-kB and other inflammatory transcription factors can modulate FGF23 expression, with some anti-inflammatory signals reducing FGF23 transcription. The exact transcription factors involved in negative regulation are context-dependent and include nuclear receptors and stress-responsive factors. This step reduces the pool of FGF mRNA available for translation.
Post-transcriptional and translational control
In simple terms: The cell prevents FGF mRNA from being made into protein or speeds up its degradation.
Negative regulation can also occur after transcription, through mechanisms such as mRNA destabilization, microRNA-mediated repression, or inhibition of translation. While specific microRNAs targeting FGF23 or FGF21 are not fully elucidated in the provided literature, general principles of post-transcriptional control apply. Autophagy and MTORC2 signaling have been implicated in fibroblast senescence and may influence the translational efficiency of FGFs. Additionally, ROS-responsive pathways can modulate protein synthesis and secretion. These post-transcriptional mechanisms provide rapid and reversible control of FGF levels.
Inhibition of FGF secretion
In simple terms: The cell blocks the release of FGF proteins into the surrounding environment.
Even if FGF protein is synthesized, its secretion can be negatively regulated. FGF23 is a secreted endocrine factor, and its release is controlled by proteolytic processing and glycosylation. Insulin has been shown to suppress FGF23 production, which may include effects on secretion. Inflammatory mediators can also affect the secretory pathway. Autophagy, a process that degrades intracellular components, may influence the availability of FGFs for secretion by targeting them for lysosomal degradation. The interplay between synthesis and secretion determines the final extracellular FGF levels.
Feedback and crosstalk with other signaling pathways
In simple terms: The reduction in FGF production can trigger further signals that reinforce or modulate the response.
Negative regulation of FGF production is embedded in complex feedback loops. For example, FGF23 itself regulates phosphate and vitamin D, which in turn can affect FGF23 production. Insulin signaling, which suppresses FGF23, is also influenced by metabolic status, creating a bidirectional relationship. FGF21, an endocrine inhibitor of sugar and alcohol appetite, is regulated by nutritional state and may feed back on metabolic pathways. Autophagy and MTORC2 signaling are interconnected with FGF-mediated processes in fibroblasts. These feedback mechanisms ensure that FGF levels are appropriately tuned to physiological demands.
Key Genes Involved in GO:0090272 negative regulation of fibroblast growth factor production
The following genes and proteins are central to the negative regulation of fibroblast growth factor production, based on verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| FGF23 | Endocrine FGF regulating phosphate and vitamin D; its production is negatively regulated by insulin and inflammation. | Target for chronic kidney disease and cardiovascular research. |
| FGF21 | Endocrine FGF inhibiting sugar and alcohol appetite; production is subject to negative regulation in metabolic contexts. | Metabolic syndrome and appetite regulation studies. |
| INSR | Insulin receptor; mediates insulin signaling that suppresses FGF23 production. | Link between insulin resistance and FGF23 levels. |
| NFKB1 | Inflammatory transcription factor; modulates FGF23 production in response to cytokines. | Inflammation-driven FGF23 regulation. |
| MTOR | Kinase in MTORC2 complex; regulates autophagy and fibroblast senescence, influencing FGF production. | Autophagy and senescence research. |
| ATG5 | Autophagy-related protein; involved in autophagy-driven fibroblast senescence and FGF regulation. | Wound healing and fibrosis models. |
| NRF2 | Transcription factor responding to ROS; modulates FGF production in pulmonary fibrosis. | Idiopathic pulmonary fibrosis therapy. |
| FGF2 | Paracrine FGF involved in fibroblast proliferation and wound healing; its production is negatively regulated in some contexts. | Fibrosis and tissue repair studies. |
| FGF10 | FGF involved in development and repair; production can be negatively regulated by inflammatory signals. | Lung and tissue regeneration research. |
| FGF18 | FGF involved in skeletal development; subject to negative regulation by metabolic signals. | Bone and cartilage research. |
| KLB | Klotho beta co-receptor for FGF21 and FGF23; influences FGF signaling and feedback. | Endocrine FGF signaling studies. |
| FGFR1 | FGF receptor 1; mediates signaling that can feedback to regulate FGF production. | FGF signaling and cancer research. |
| PPARG | Nuclear receptor; may suppress FGF production in metabolic tissues. | Metabolic regulation of FGFs. |
| SIRT1 | Deacetylase; linked to metabolic regulation and potential suppression of FGF23. | Aging and metabolic research. |
| IL6 | Pro-inflammatory cytokine; can stimulate FGF23, but anti-inflammatory signals may suppress it. | Inflammation and FGF23 regulation. |
| TNF | Pro-inflammatory cytokine; modulates FGF23 production in inflammatory states. | Chronic kidney disease and inflammation. |
| BECN1 | Autophagy regulator; influences fibroblast senescence and FGF production. | Autophagy and fibrosis research. |
| MAP1LC3B | Autophagy marker; involved in autophagic regulation of FGF-producing cells. | Autophagy studies in fibroblasts. |
How Is negative regulation of fibroblast growth factor production Regulated?
The negative regulation of FGF production is controlled by multiple signaling pathways. Insulin signaling is a direct negative regulator of FGF23 production, where insulin receptor activation suppresses FGF23 gene expression. Inflammatory pathways, particularly those involving NF-kB, modulate FGF23 production in response to cytokines, with anti-inflammatory signals potentially reducing FGF23 levels. Autophagy and MTORC2 signaling regulate fibroblast senescence and may influence FGF production in tissue remodeling. Reactive oxygen species (ROS) activate Nrf2 signaling, which can suppress FGF production in idiopathic pulmonary fibrosis. Additionally, metabolic status and nutritional cues regulate FGF21 production, which is subject to negative feedback. These pathways converge on transcriptional and post-transcriptional mechanisms to fine-tune FGF levels.
negative regulation of fibroblast growth factor production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FGF23 | Chronic kidney disease, hyperphosphatemia | KO and knock-in mouse models; CRISPR point mutations in FGF23 promoter. |
| FGF21 | Heart failure with preserved ejection fraction, metabolic syndrome | Overexpression and KO models; CRISPR knock-in of human FGF21 variants. |
| NRF2 | Idiopathic pulmonary fibrosis | KO and overexpression models; ROS-responsive delivery in mice. |
| MTOR | Fibroblast senescence, fibrosis | Conditional KO; CRISPR point mutations in MTORC2 components. |
| ATG5 | Wound healing, fibrosis | KO and tagged knock-in for autophagy flux. |
Chronic kidney disease and FGF23
FGF23 is a key regulator of phosphate homeostasis, and its production is often elevated in chronic kidney disease (CKD). Negative regulation of FGF23 production is impaired in CKD, contributing to hyperphosphatemia and cardiovascular complications. Insulin resistance, common in CKD, may further dysregulate FGF23 suppression. Inflammatory cytokines also stimulate FGF23 production, overriding negative regulatory mechanisms. Targeting the pathways that negatively regulate FGF23 could offer therapeutic benefits in CKD.
Heart failure with preserved ejection fraction (HFpEF)
FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice. Negative regulation of FGF21 production may exacerbate HFpEF, while enhancing FGF21 signaling could be protective. Understanding how FGF21 production is suppressed in metabolic and cardiac stress conditions is therefore relevant for HFpEF therapy.
Idiopathic pulmonary fibrosis (IPF)
ROS-responsive liposomes targeting Nrf2 signaling have been used to treat IPF in preclinical models. Nrf2 activation can negatively regulate FGF production, reducing fibrosis. Thus, the negative regulation of FGF production is a potential therapeutic axis in IPF.
Metabolic disorders and appetite regulation
FGF21 is an endocrine inhibitor of sugar and alcohol appetite, and its production is negatively regulated by nutritional and metabolic signals. Dysregulation of FGF21 production contributes to metabolic syndrome and alcohol use disorders. Modulating the negative regulation of FGF21 could influence appetite and metabolic health.
From negative regulation of fibroblast growth factor production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate FGF23 production? | CRISPR knockout of gene X in UMR-106 or HEK293 cells, measure FGF23 by ELISA. |
| Does a specific point mutation in INSR affect FGF23 suppression? | CRISPR point mutation knock-in of INSR variants in hepatocyte-like cells. |
| Can overexpression of NRF2 suppress FGF production in fibrosis? | CRISPR overexpression (CRISPRa) of NRF2 in lung fibroblasts. |
| What is the role of autophagy in FGF-producing fibroblasts? | CRISPR knockout of ATG5 or BECN1 in primary fibroblasts, measure FGF secretion. |
| Does FGF21 knock-in of human variant alter appetite regulation? | CRISPR knock-in of human FGF21 variant in mouse liver. |
| Can tagged knock-in of FGF23 reveal secretion dynamics? | CRISPR knock-in of fluorescent tag into endogenous FGF23 locus. |
How to Study the negative regulation of fibroblast growth factor production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screening | Loss-of-function effects on FGF production | Identify negative regulators of FGF23. |
| RNA-seq | Transcriptional changes in FGF genes | Measure insulin-mediated suppression of FGF23. |
| ELISA | Secreted FGF protein levels | Quantify FGF23 in cell culture media. |
| Western blot | Intracellular FGF protein levels | Assess FGF21 expression. |
| Luciferase reporter assay | FGF promoter activity | Test transcriptional suppression. |
| CRISPR activation (CRISPRa) | Overexpression of candidate genes | Test NRF2-mediated FGF suppression. |
| Autophagy flux assay | Autophagic degradation | Study ATG5 role in FGF-producing fibroblasts. |
| Phosphate uptake assay | FGF23 bioactivity | Functional validation in renal cells. |
CRISPR screening for regulators of FGF production
Genome-wide CRISPR knockout or activation screens can identify genes that negatively regulate FGF production. Cells expressing a reporter under the control of an FGF promoter (e.g., FGF23 or FGF21) can be subjected to library screening, and hits validated by targeted knockout. This approach is unbiased and scalable.
Transcriptomic and proteomic analysis
RNA-seq and proteomics can quantify changes in FGF mRNA and protein levels upon genetic or pharmacological perturbation. For example, insulin treatment reduces FGF23 mRNA, which can be detected by RNA-seq. Proteomics of secreted FGFs can reveal effects on secretion.
Functional assays for FGF bioactivity
FGF bioactivity can be measured using reporter cell lines or downstream phosphorylation assays. For FGF23, phosphate uptake assays in renal cells can assess bioactivity. For FGF21, glucose uptake or appetite-related neuronal assays can be used.
Imaging and localization studies
Fluorescent tagging of FGFs via CRISPR knock-in allows live-cell imaging of FGF trafficking and secretion. This can reveal how negative regulators affect FGF localization and release.
How CRISPR Can Be Used to Study GO:0090272 negative regulation of fibroblast growth factor production
Knockout
CRISPR knockout of candidate negative regulators (e.g., INSR, NRF2) can determine whether they are necessary for suppressing FGF production. For example, knocking out INSR in hepatocytes would test if insulin-mediated FGF23 suppression is lost. Knockout of ATG5 can reveal the role of autophagy in FGF regulation.
Point Mutation
CRISPR point mutation knock-in can model disease-associated variants in genes like FGF23 or INSR. For instance, introducing a kinase-dead mutation in INSR would test its role in FGF23 suppression. Point mutations in the FGF23 promoter can identify regulatory elements.
Knock-in
CRISPR knock-in of reporter tags (e.g., GFP) into endogenous FGF loci enables real-time tracking of FGF production and secretion. Knock-in of human FGF21 variants into mouse models can test their effects on appetite and metabolism. Knock-in of tagged NRF2 can reveal its dynamics in fibrosis.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression can test sufficiency of candidate genes in suppressing FGF production. Overexpressing NRF2 in lung fibroblasts may reduce FGF production and fibrosis. Overexpressing FGF21 can protect against HFpEF.
How EDITGENE Supports negative regulation of fibroblast growth factor production Research
Researchers studying negative regulation of fibroblast growth factor production-related genes often need to determine whether a candidate gene is causally involved in suppressing FGF biosynthesis or secretion. This requires precise genetic manipulation, which can be achieved through CRISPR-based knockout, point mutation, knock-in, or overexpression models. EDITGENE provides comprehensive services to support such investigations, from cell line generation to library screening and bioinformatics analysis.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of fibroblast growth factor production research.
Frequently Asked Questions About negative regulation of fibroblast growth factor production
What is GO:0090272?
GO:0090272 is the Gene Ontology term for negative regulation of fibroblast growth factor production, defined as any process that decreases the rate, frequency or extent of FGF appearance due to biosynthesis or secretion following a cellular stimulus.
What genes are involved in negative regulation of fibroblast growth factor production?
Key genes include INSR, which mediates insulin suppression of FGF23, NRF2, which responds to ROS to suppress FGF production, and ATG5, involved in autophagy-driven regulation.
How does insulin suppress FGF23 production?
Insulin signaling through the insulin receptor suppresses FGF23 gene expression, as demonstrated in cell and animal models.
What is the role of inflammation in FGF23 production?
Inflammatory cytokines can stimulate FGF23 production, but anti-inflammatory signals may contribute to its negative regulation.
Can CRISPR be used to study negative regulation of FGF production?
Yes, CRISPR knockout, knock-in, and overexpression models are powerful tools to dissect the causal roles of genes in FGF regulation.
What diseases are associated with dysregulated FGF production?
Chronic kidney disease, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, and metabolic disorders are linked to altered FGF production.
How does FGF21 regulate appetite?
FGF21 acts as an endocrine inhibitor of sugar and alcohol appetite, and its production is negatively regulated by nutritional signals.
What is the link between autophagy and FGF production?
Autophagy drives fibroblast senescence through MTORC2 regulation and can influence FGF production in tissue remodeling.
What experimental models are used to study GO:0090272?
Common models include CRISPR knockout cell lines, knock-in mice, and overexpression systems, combined with RNA-seq, ELISA, and imaging.
How can EDITGENE help with my research on FGF regulation?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression, library screening, and bioinformatics services tailored to FGF regulation studies.
Conclusion
GO:0090272, negative regulation of fibroblast growth factor production, is a critical biological process that controls the levels of FGFs in response to diverse stimuli. Dysregulation of this process contributes to major human diseases, including chronic kidney disease, heart failure, and fibrosis. Understanding the molecular mechanisms and key genes involved, such as INSR, NRF2, and ATG5, offers opportunities for therapeutic intervention. CRISPR-based models are indispensable for dissecting these pathways, and EDITGENE provides comprehensive services to support such research. By leveraging precise genetic tools and bioinformatics, researchers can accelerate discoveries in FGF biology and translate them into clinical benefits.
References
- 1. Zhang K et al.. 2025. FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice.. Nat Commun 16(1):1661 PMID: 39955281
- 3. Bernard M et al.. 2020. Autophagy drives fibroblast senescence through MTORC2 regulation.. Autophagy 16(11):2004-2016 PMID: 31931659
- 4. Qiang L et al.. 2021. Keratinocyte autophagy enables the activation of keratinocytes and fibroblastsand facilitates wound healing.. Autophagy 17(9):2128-2143 PMID: 32866426
- 5. Francis C et al.. 2016. Inflammation regulates fibroblast growth factor 23 production.. Curr Opin Nephrol Hypertens 25(4):325-32 PMID: 27191351
- 6. Bär L et al.. 2018. Insulin suppresses the production of fibroblast growth factor 23 (FGF23).. Proc Natl Acad Sci U S A 115(22):5804-5809 PMID: 29760049
- 7. Liu J et al.. 2022. ROS-responsive liposomes as an inhaled drug delivery nanoplatform for idiopathic pulmonary fibrosis treatment via Nrf2 signaling.. J Nanobiotechnology 20(1):213 PMID: 35524280
- 8. von Holstein-Rathlou S et al.. 2019. Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite.. J Physiol 597(14):3539-3548 PMID: 30921473
