The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis

Nuclear factor of activated T cells (NFAT) transcription factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway. Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype. Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor.

• Publication year

  2000

• Venue

  Journal of Experimental Medicine

• Publication date

  2000-01-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/JEM.191.1.9PMID 10620601PMCID 2195796
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Prognostic significance of nuclear DNA content in chondrosarcoma.

  2000cited by this paper
• Bone development.

  2000cited by this paper
• Rad18 is required for DNA repair and checkpoint responses in fission yeast.

  1999cited by this paper
• Chondrosarcoma of bone: an assessment of outcome.

  1999cited by this paper
• A Quadripotential Mesenchymal Progenitor Cell Isolated from the Marrow of an Adult Mouse

  1999cited by this paper
• Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart.

  1999cited by this paper
• Multilineage potential of adult human mesenchymal stem cells.

  1999cited by this paper
• The Chondrogenic Potential of Human Bone-Marrow-Derived Mesenchymal Progenitor Cells*

  1998cited by this paper
• The transcription factor NF-ATc is essential for cardiac valve formation

  1998cited by this paper
• Activation and cellular localization of the cyclosporine A-sensitive transcription factor NF-AT in skeletal muscle cells.

  1998cited by this paper
• Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum

  1998cited by this paper
• The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation.

  1998cited by this paper
• In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells.

  1998cited by this paper
• Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton.

  1998cited by this paper
• A calcineurin-dependent transcriptional pathway for cardiac hypertrophy.

  1998cited by this paper
• Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development.

  1998cited by this paper
• Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia.

  1998cited by this paper
• Cartilage‐Derived Morphogenetic Proteins and Osteogenic Protein‐1 Differentially Regulate Osteogenesis

  1998cited by this paper
• Chondrogenic Differentiation of Cultured Human Mesenchymal Stem Cells from Marrow

  1998cited by this paper
• The transcription factor NFAT4 is involved in the generation and survival of T cells.

  1998cited by this paper
• The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production.

  1998cited by this paper
• Three High Mobility Group-like Sequences within a 48-Base Pair Enhancer of the Col2a1 Gene Are Required for Cartilage-specific Expression in Vivo *

  1998cited by this paper
• A potential role for the nuclear factor of activated T cells family of transcriptional regulatory proteins in adipogenesis.

  1998cited by this paper
• Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc.

  1998cited by this paper
• Differential activation of transcription factors induced by Ca2+ response amplitude and duration

  1997cited by this paper
• Nuclear Export of NF-ATc Enhanced by Glycogen Synthase Kinase-3

  1997cited by this paper
• Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations.

  1997cited by this paper
• Transcription factors of the NFAT family: regulation and function.

  1997cited by this paper
• Cartilage-derived morphogenetic proteins

  1997cited by this paper
• Developmental Restriction of Embryonic Calvarial Cell Populations as Characterized by Their In Vitro Potential for Chondrogenic Differentiation

  1997cited by this paper
• The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells.

  1997cited by this paper
• Down-regulation of IL-4 gene transcription and control of Th2 cell differentiation by a mechanism involving NFAT1.

  1997cited by this paper
• Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction.

  1997cited by this paper
• An Enhanced Immune Response in Mice Lacking the Transcription Factor NFAT1

  1996cited by this paper
• NF-AT-Driven Interleukin-4 Transcription Potentiated by NIP45

  1996cited by this paper
• The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4.

  1996cited by this paper
• Mouse Eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response.

  1996cited by this paper
• Fibroblast growth factor receptor 3 is a negative regulator of bone growth.

  1996cited by this paper
• Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein

  1996cited by this paper
• Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice.

  1996cited by this paper
• Differentiation potential of conditionally immortalized mesenchymal progenitor cells from adult marrow of a H‐2Kb‐tsA58 transgenic mouse

  1996cited by this paper
• NFATc3, a Lymphoid-specific NFATc Family Member That Is Calcium-regulated and Exhibits Distinct DNA Binding Specificity (*)

  1995cited by this paper
• Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo.

  1995cited by this paper
• Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene.

  1995cited by this paper
• Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins.

  1995cited by this paper
• Human MHC class II gene transcription directed by the carboxyl terminus of CIITA, one of the defective genes in type II MHC combined immune deficiency.

  1995cited by this paper
• Toward a molecular understanding of skeletal development.

  1995cited by this paper
• Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11.

  1995cited by this paper
• Chondrosarcoma of bone. A clinical and DNA flow cytometric study.

  1995cited by this paper
• NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus

  1995cited by this paper
• Developmental restriction of embryonic mesen chymal stem cells as characterized by their in vitro potential for differentiation

  1995cited by this paper
• Cytogenetics of Bone and Soft Tissue Tumors

  1995cited by this paper
• The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms.

  1994cited by this paper
• Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia.

  1994cited by this paper
• Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia

  1994cited by this paper
• NF-AT components define a family of transcription factors targeted in T-cell activation

  1994cited by this paper
• Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene.

  1994cited by this paper
• Limb alterations in brachypodism mice due to mutations in a new member of the TGFβ-superfamily

  1994cited by this paper
• Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development.

  1994cited by this paper
• The mouse collagen X gene: complete nucleotide sequence, exon structure and expression pattern.

  1993cited by this paper
• In situ hybridization studies suggest a role for the basic region‐leucine zipper protein hXBP‐1 in exocrine gland and skeletal development during mouse embryogenesis

  1993cited by this paper
• p53 expression and its relationship to DNA alterations in bone and soft tissue sarcomas.

  1993cited by this paper
• The granulocyte-macrophage colony-stimulating factor/interleukin 3 locus is regulated by an inducible cyclosporin A-sensitive enhancer.

  1993cited by this paper
• Possible Association of p53 Overexpression and Mutation with High‐Grade Chondrosarcoma

  1993cited by this paper
• Isolation of the cyclosporin-sensitive T cell transcription factor NFATp.

  1993cited by this paper
• Role of insulin-like growth factors in embryonic and postnatal growth.

  1993cited by this paper
• Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation

  1992cited by this paper
• Specific hybridization probes for mouse type I, II, III and IX collagen mRNAs.

  1991cited by this paper
• Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A

  1991cited by this paper
• Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse.

  1991cited by this paper
• H‐2Kb‐tsA58トランスジェニックマウスから直接に無限増殖細胞系を得る方法

  1991cited by this paper
• Cartilage Molecular Aspects

  1991cited by this paper
• The ideal scientist described.

  1990cited by this paper
• Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur

  1990cited by this paper
• Stimulation of the expression of osteogenic and chondrogenic phenotypes in vitro by osteogenin.

  1989cited by this paper
• Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation.

  1989cited by this paper
• Quantitative analysis of collagen expression in embryonic chick chondrocytes having different developmental fates.

  1989cited by this paper
• Contingent genetic regulatory events in T lymphocyte activation.

  1989cited by this paper
• Identification of a putative regulator of early T cell activation genes.

  1988influential reference
• Bone development.

  1988cited by this paper
• Characterization of antigen receptor response elements within the interleukin-2 enhancer

  1988cited by this paper
• Novel regulators of bone formation: molecular clones and activities.

  1988cited by this paper
• A system of staging musculoskeletal neoplasms.

  1986cited by this paper
• A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma

  1986cited by this paper
• The prognostic significance of nuclear DNA content in chondrosarcoma.

  1980cited by this paper
• Chondrosarcoma of Bone.

  1943cited by this paper

• Leveraging single cell multiomic analyses to identify gene regulatory networks that drive human articular cartilage cell fate.

  2026cites this paper
• Integrated mRNA and miRNA Analysis Reveals Layer-Specific Mechanisms of Antler Yield Variation in Sika Deer

  2025cites this paper
• Single-nucleus transcriptomics decodes the link between aging and lumbar disc herniation

  2025cites this paper
• Persistent open chromatin state in early-life stress-activated cells of the VTA

  2025cites this paper
• A Novel Homozygous Six Base Pair Deletion Found in the NFATC2 Gene in a Patient with EBV-Associated Lymphoproliferation

  2024cites this paper
• Leveraging single cell multiomic analyses to identify factors that drive human chondrocyte cell fate

  2024cites this paper
• The natural flavone quercetin: An extensive analysis of its pharmacological mechanisms and medicinal prospects

  2024cites this paper
• Primary vascular tumors of bone: a comprehensive literature review on classification, diagnosis and treatment.

  2024cites this paper
• NFATC1 and NFATC2 expression patterns in human osteochondromas

  2023cites this paper
• Targeting CaN/NFAT in Alzheimer’s brain degeneration

  2023cites this paper
• Rare diseases of epigenetic origin: Challenges and opportunities

  2023cites this paper
• RNF125, transcriptionally regulated by NFATC2, alleviates osteoarthritis via inhibiting the Wnt/β-catenin signaling pathway through degrading TRIM14.

  2023cites this paper
• An Overview of the Pharmacological Activities of Scopoletin against Different Chronic Diseases.

  2022cites this paper
• Aging and Obesity Prime the Methylome and Transcriptome of Adipose Stem Cells for Disease and Dysfunction

  2022cites this paper
• Physosmotic Induction of Chondrogenic Maturation Is TGF-β Dependent and Enhanced by Calcineurin Inhibitor FK506

  2022cites this paper
• Role of nuclear factor of activated T cells in chondrogenesis osteogenesis and osteochondroma formation

  2022cites this paper
• Human germline biallelic complete NFAT1 deficiency causes the triad of progressive joint contractures, osteochondromas, and susceptibility to B cell malignancy

  2022cites this paper
• Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B cell malignancy.

  2022cites this paper
• The role of Ca2+/Calcineurin/NFAT signalling pathway in osteoblastogenesis

  2021cites this paper
• Role of Nuclear Factor of Activated T Cells (NFAT) Pathway in Regulating Autophagy and Inflammation in Retinal Pigment Epithelial Cells

  2021cites this paper
• A unique epithelioid vascular neoplasm of bone characterized by EWSR1/FUS‐NFATC1/2 fusions

  2021cites this paper
• Neural EGFL like 1 as a potential pro-chondrogenic, anti-inflammatory dual-functional disease-modifying osteoarthritis drug.

  2020cites this paper
• Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

  2020cites this paper
• Nuclear factor of activated T cells 1 and 2 are required for vertebral homeostasis

  2020cites this paper
• Wnt-signaling in skeletal development.

  2019cites this paper
• Co-Stimulation–Induced AP-1 Activity is Required for Chromatin Opening During T Cell Activation

  2019influential citation
• EWSR1/FUS - NFATc2 rearranged round cell sarcoma: Clinicopathological series of four cases and literature review.

  2019cites this paper
• AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation

  2019cites this paper
• Timing metabolism in cartilage and bone: links between circadian clocks and tissue homeostasis.

  2019cites this paper
• Single-cell gene regulatory network analysis reveals new melanoma cell states and transition trajectories during phenotype switching

  2019cites this paper
• Atoh8 acts as a regulator of chondrocyte proliferation and differentiation in endochondral bones

  2019cites this paper
• Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment

  2019cites this paper
• BCPA {N,N′-1,4-Butanediylbis[3-(2-chlorophenyl)acrylamide]} Inhibits Osteoclast Differentiation through Increased Retention of Peptidyl-Prolyl cis-trans Isomerase Never in Mitosis A-Interacting 1

  2018cites this paper
• Nerve growth factor prevents arsenic‐induced toxicity in PC12 cells through the AKT/GSK‐3β/NFAT pathway

  2018influential citation
• Gene expression profiling: identification of gene expression in human MSC chondrogenic differentiation.

  2018cites this paper
• Transcriptional network systems in cartilage development and disease

  2018cites this paper
• Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo

  2018cites this paper
• Histone hypo-acetylation of Sox9 mediates nicotine-induced weak cartilage repair by suppressing BMSC chondrogenic differentiation

  2018cites this paper
• Transcriptional network systems in cartilage development and disease

  2018cites this paper
• Curcumin in Cancer Prevention

  2018cites this paper
• Opening the Black Box of Immunosuppression

  2018cites this paper
• Nfatc1 Is a Functional Transcriptional Factor Mediating Nell-1-Induced Runx3 Upregulation in Chondrocytes

  2018cites this paper
• Cross talk among PMCA, calcineurin and NFAT transcription factors in control of calmodulin gene expression in differentiating PC12 cells.

  2017cites this paper
• SALL 4 and NFATC 2 : two major actors of interstitial 20 q 13 . 2 duplication

  2017cites this paper
• Methylation-mediated silencing of miR-124 facilitates chondrogenesis by targeting NFATc1 under hypoxic conditions.

  2017cites this paper
• NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer’s Disease

  2017cites this paper
• Role of IRF4-Mediated Inflammation: Implication in Neurodegenerative Diseases.

  2017cites this paper
• NFAT restricts osteochondroma formation from entheseal progenitors.

  2016cites this paper
• Cell cycle and apoptosis regulation by NFAT transcription factors: new roles for an old player

  2016cites this paper
• Wnt Signaling in Cartilage Development

  2016cites this paper
• Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome.

  2016cites this paper
• Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome.

  2016cites this paper
• NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

  2016cites this paper
• Physicochemical and Biomechanical Stimuli in Cell-Based Articular Cartilage Repair

  2015cites this paper
• Associations between Hox genes molecular evolution and the evolution of morphological diversity in Squamata and Marsupialia

  2015cites this paper
• Effects of Different Levels of Protein Supplements in the Diet of Early-Weaned Yaks on Growth Performance, Intestinal Development, and Immune Response to Tuberculosis

  2015cites this paper
• The Role of NFATc1 on Osteoblastic Differentiation in Human Periodontal Ligament Cells

  2015cites this paper
• Nfatc2 and Tob1 Have Non-Overlapping Function in T Cell Negative Regulation and Tumorigenesis

  2014cites this paper
• Integrative Genomic and Transcriptomic Analysis Identified Candidate Genes Implicated in the Pathogenesis of Hepatosplenic T-Cell Lymphoma

  2014cites this paper
• Etiology of Hip Osteoarthritis

  2014cites this paper
• FK 506 protects against articular cartilage collagenous extracellular matrix degradation

  2014cites this paper
• FK506 protects against articular cartilage collagenous extra-cellular matrix degradation.

  2014cites this paper
• SALL4 and NFATC2: two major actors of interstitial 20q13.2 duplication.

  2014cites this paper
• Role of Ca/CaN/NFAT signaling in IL-4 expression by splenic lymphocytes exposed to phthalate (2-ethylhexyl) ester in spleen lymphocytes

  2014cites this paper
• NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

  2014cites this paper
• The role of microRNA in the development of pulmonary arterial hypertension: studies in cell culture and animal models.

  2014cites this paper
• NFATs are good for your cartilage!

  2014cites this paper
• The role of canonical and non-canonical WNT signalling pathways in load induced cartilage degradation

  2014cites this paper
• Calcineurin/NFAT Signaling Represses Genes Vamp1 and Vamp2 via PMCA-Dependent Mechanism during Dopamine Secretion by Pheochromocytoma Cells

  2014cites this paper
• NFATc1 and NFATc2 repress spontaneous osteoarthritis

  2013influential citation
• Development of a rapid diagnostic screen for telomerase mutations associated with immunosuppressive therapy failure in patients with aplastic anaemia

  2013cites this paper
• Bacterial infection of macrophages induces decrease in refractive index

  2013cites this paper
• The transcription factor NFAT1 induces apoptosis through cooperation with Ras/Raf/MEK/ERK pathway and upregulation of TNF-α expression.

  2013cites this paper
• Notch suppresses nuclear factor of activated T cells (NFAT) transactivation and Nfatc1 expression in chondrocytes.

  2013cites this paper
• Nuclear factor of activated T-cells 1 increases sensitivity of v-myb transformed monoblasts to all-trans retinoic acid.

  2013cites this paper
• NFAT1 C-Terminal Domains Are Necessary but Not Sufficient for Inducing Cell Death

  2012cites this paper
• Role of NFAT (Nuclear Factor of Activated T Cells)Transcription Factors in Hematopoiesis

  2012cites this paper
• Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis

  2012cites this paper
• Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1

  2012cites this paper
• Primary Neoplasms of Bones in Mice

  2012cites this paper
• NFATc1/αA: The other Face of NFAT Factors in Lymphocytes

  2012cites this paper
• Characteristic Markers of the WNT Signaling Pathways Are Differentially Expressed in Osteoarthritic Cartilage

  2012cites this paper
• GnRH regulation of Jun and Atf3 requires calcium, calcineurin, and NFAT.

  2012cites this paper
• NIP45 negatively regulates RANK ligand induced osteoclast differentiation

  2012cites this paper
• Étude de la régulation transcriptionnelle du gène Indian Hedgehog et de son rôle dans l'ostéoarthrose

  2011cites this paper
• High extracellular calcium-induced NFATc3 regulates the expression of receptor activator of NF-κB ligand in osteoblasts.

  2011cites this paper
• Enhanced Chromatin Accessibility and Recruitment of JUNB Mediate the Sustained IL-4 Expression in NFAT1 Deficient T Helper 2 Cells

  2011cites this paper
• Dietary supplementation with Atractylodes Macrophala Koidz polysaccharides ameliorate metabolic status and improve immune function in early-weaned pigs ☆

  2011cites this paper
• Nfatc2 is a primary response gene of nell‐1 regulating chondrogenesis in ATDC5 cells

  2011cites this paper
• Nfat1 regulates adult articular chondrocyte function through its age‐dependent expression mediated by epigenetic histone methylation

  2011cites this paper
• Interferon Regulatory Factor 2 Binding Protein 2 Is a New NFAT1 Partner and Represses Its Transcriptional Activity

  2011influential citation
• Negative cross talk between NFAT1 and Stat5 signaling in breast cancer.

  2011cites this paper
• NFATc1 in inflammatory and musculoskeletal conditions.

  2010cites this paper
• WNT5A regulates chondrocyte differentiation through differential use of the CaN/NFAT and IKK/NF-kappaB pathways.

  2010cites this paper
• Spatial and temporal regulation of gene expression in the mammalian growth plate.

  2010cites this paper
• NFAT3 transcription factor inhibits breast cancer cell motility by targeting the Lipocalin 2 gene

  2010cites this paper
• Transcriptional regulation of bone and joint remodeling by NFAT

  2010cites this paper
• 26 – Cell Differentiation in the Skeleton

  2009cites this paper
• Expression, localisation and functional activation of NFAT-2 in normal human skin, psoriasis, and cultured keratocytes.

  2009cites this paper
• Stromal cells.

  2009cites this paper