Osteoarthritic chondrocyte hypertrophy (Homo sapiens)

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211111154ChondrocyteAKT and MAPK proteins interact with transcription factors which regulate gene expressionProlyl 4-hydroxylase uses molecular oxygen to hydroxylate HIF1AL-thyroxineCNMDO2DIO2Vascularization3, 13Endothelial cell proliferationRUNX2TriiodothyronineMigrationCEBPBHypertrophyTube formationEPAS1COL10A1HypoxiaMMP13CEBPB5JUNDCOL3A1JUNBKDR9RELAFOSCOL10A1PRKCAJUNNFKB1COL1A1STAT3JAK2PFOSL2HIF1AIBSPRELB8DDR2MAPK3MAPK1FOSL1NGFCCN28SPP1COL2A1FOSBVEGFAVEGFA14RUNX212FGFR1NGFFGF237FGFR2FGFR3FGFR4LAMTOR1NTRK1PIK3CAMAPK1MAPK3AKT1AKT2AKT3RASCOL10A16VEGFAMMP13SOX96AGC10COL2A1Hypoxia drives accumulation ofintracellular HIF1AHIF1A is hydroxylated at Pro402 and Pro564, making it a target for pVHL.GANCCOL2A1ACANVEGFAHIF1AOHARNTProlyl 4-hydroxylase11VHLHIF1AUbHIF1AHIF1AARNTHIF1AARNTChondrocyteNucleus


Description

Hypoxia in osteoarthritis (OA) leads to low oxygen levels in cartilage, activating hypoxia-inducible factors (HIFs). Angiogenesis occurs in response to hypoxia, stimulating the formation of new blood vessels. Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. Dysregulation of the canonical FGF signalling pathway disrupts chondrocyte proliferation and differentiation. In OA, aberrant FGF signalling contributes to the hypertrophic chondrocyte phenotype. This phenotype is associated with increased cell size, altered gene expression and matrix degradation. Understanding these interactions may provide therapeutic insights for the treatment of OA. The pathway is based on Figure 5 of the paper by Ellen G. J. Ripmeester et al. (2018).

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Bibliography

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  1. Ripmeester EGJ, Timur UT, Caron MMJ, Welting TJM; ''Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis.''; Front Bioeng Biotechnol, 2018 PubMed Europe PMC Scholia
  2. Zhou S, Xie Y, Li W, Huang J, Wang Z, Tang J, Xu W, Sun X, Tan Q, Huang S, Luo F, Xu M, Wang J, Wu T, Chen L, Chen H, Su N, Du X, Shen Y; ''Conditional Deletion of Fgfr3 in Chondrocytes leads to Osteoarthritis-like Defects in Temporomandibular Joint of Adult Mice.''; Sci Rep, 2016 PubMed Europe PMC Scholia
  3. Borzí RM, Olivotto E, Pagani S, Vitellozzi R, Neri S, Battistelli M, Falcieri E, Facchini A, Flamigni F, Penzo M, Platano D, Santi S, Marcu KB; ''Matrix metalloproteinase 13 loss associated with impaired extracellular matrix remodeling disrupts chondrocyte differentiation by concerted effects on multiple regulatory factors.''; Arthritis Rheum, 2010 PubMed Europe PMC Scholia
  4. Christa Maes, Geert Carmeliet, Ernestina Schipani; ''Hypoxia-driven pathways in bone development, regeneration and disease''; https://doi.org/10.1038/nrrheum.2012.36, 2012 PubMed Europe PMC Scholia
  5. Nagase H, Nagasawa Y, Tachida Y, Sakakibara S, Okutsu J, Suematsu N, Arita S, Shimada K; ''Deiodinase 2 upregulation demonstrated in osteoarthritis patients cartilage causes cartilage destruction in tissue-specific transgenic rats.''; Osteoarthritis Cartilage, 2013 PubMed Europe PMC Scholia
  6. Hirata M, Kugimiya F, Fukai A, Saito T, Yano F, Ikeda T, Mabuchi A, Sapkota BR, Akune T, Nishida N, Yoshimura N, Nakagawa T, Tokunaga K, Nakamura K, Chung UI, Kawaguchi H; ''C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes.''; Hum Mol Genet, 2012 PubMed Europe PMC Scholia
  7. Pesesse L, Sanchez C, Delcour JP, Bellahcène A, Baudouin C, Msika P, Henrotin Y; ''Consequences of chondrocyte hypertrophy on osteoarthritic cartilage: potential effect on angiogenesis.''; Osteoarthritis Cartilage, 2013 PubMed Europe PMC Scholia
  8. Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba S, Nishida N, Akune T, Yoshimura N, Nakagawa T, Nakamura K, Tokunaga K, Chung UI, Kawaguchi H; ''Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.''; Nat Med, 2010 PubMed Europe PMC Scholia
  9. Bomer N, den Hollander W, Ramos YF, Bos SD, van der Breggen R, Lakenberg N, Pepers BA, van Eeden AE, Darvishan A, Tobi EW, Duijnisveld BJ, van den Akker EB, Heijmans BT, van Roon-Mom WM, Verbeek FJ, van Osch GJ, Nelissen RG, Slagboom PE, Meulenbelt I; ''Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis.''; Ann Rheum Dis, 2015 PubMed Europe PMC Scholia
  10. Raimann A, Ertl DA, Helmreich M, Sagmeister S, Egerbacher M, Haeusler G; ''Fibroblast growth factor 23 and Klotho are present in the growth plate.''; Connect Tissue Res, 2013 PubMed Europe PMC Scholia
  11. Bianchi A, Guibert M, Cailotto F, Gasser A, Presle N, Mainard D, Netter P, Kempf H, Jouzeau JY, Reboul P; ''Fibroblast Growth Factor 23 drives MMP13 expression in human osteoarthritic chondrocytes in a Klotho-independent manner.''; Osteoarthritis Cartilage, 2016 PubMed Europe PMC Scholia
  12. Cummins EP, Taylor CT; ''Hypoxia-responsive transcription factors.''; Pflugers Arch, 2005 PubMed Europe PMC Scholia
  13. Markway BD, Cho H, Johnstone B; ''Hypoxia promotes redifferentiation and suppresses markers of hypertrophy and degeneration in both healthy and osteoarthritic chondrocytes.''; Arthritis Res Ther, 2013 PubMed Europe PMC Scholia
  14. Orfanidou T, Iliopoulos D, Malizos KN, Tsezou A; ''Involvement of SOX-9 and FGF-23 in RUNX-2 regulation in osteoarthritic chondrocytes.''; J Cell Mol Med, 2009 PubMed Europe PMC Scholia
  15. Chen LF, Greene WC; ''Regulation of distinct biological activities of the NF-kappaB transcription factor complex by acetylation.''; J Mol Med (Berl), 2003 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
135160view00:12, 7 August 2024EweitzStandardize pathway shape
135159view00:11, 7 August 2024EweitzEconomize layout
134527view14:30, 22 July 2024EgonwRemoved template comments
128732view02:58, 21 February 2024EweitzUpgrade disease node
128546view22:28, 11 February 2024EweitzOntology Term : 'hypertrophic chondrocyte' added !
128545view22:23, 11 February 2024EweitzEconomize layout
128544view22:13, 11 February 2024EweitzModified title
128543view22:12, 11 February 2024EweitzLabel cell type (chondrocyte), nucleus
128542view22:02, 11 February 2024EweitzOntology Term : 'chondrocyte' added !
128541view21:55, 11 February 2024EweitzNudge membrane proteins towards middle
128540view21:54, 11 February 2024EweitzEconomize layout
128539view19:59, 11 February 2024EweitzFix site-PathVisio graphics discrepancy
128538view19:58, 11 February 2024EweitzEconomize layout
128537view19:42, 11 February 2024EweitzEconomize layout
128536view18:20, 11 February 2024EweitzEconomize layout
126811view07:28, 23 June 2023Uday asAdded WikiData identifiers in the comment section to the indications.
126805view15:08, 22 June 2023Uday aschanged some protein identifiers to uniprot_trembl (making sure it's the Swissprot ID)
126787view13:51, 22 June 2023DeSlChanged last unknown DataNode type to Pathway
126786view13:50, 22 June 2023DeSlChanged some processes to pathway DataNodes
126785view13:48, 22 June 2023DeSlUpdated description
126733view08:29, 16 June 2023Phil HitModified title
126718view13:47, 15 June 2023Phil Hit1. added references

2. adapted hypoxia pathway

3. changed label nodes to data nodes
126717view12:45, 15 June 2023Phil HitModified title
126689view11:02, 13 June 2023Phil HitModified title
126688view10:52, 13 June 2023Phil Hit
126668view21:38, 9 June 2023Phil HitModified description
126667view21:14, 9 June 2023Phil Hit
126666view21:14, 9 June 2023Phil HitAdded original reference that the pathway is based on
126665view21:04, 9 June 2023Phil HitOntology Term : 'mitogen activated protein kinase signaling pathway' added !
126664view21:03, 9 June 2023Phil HitOntology Term : 'fibroblast growth factor signaling pathway' added !
126663view21:00, 9 June 2023Phil HitOntology Term : 'osteoarthritis' added !
126662view20:59, 9 June 2023Phil HitOntology Term : 'thyroid hormone biosynthetic pathway' added !
126661view20:58, 9 June 2023Phil HitOntology Term : 'hypoxia inducible factor pathway' added !
126660view20:42, 9 June 2023Phil HitFormal corrections to title, removal of typos, shortening of names
126659view20:31, 9 June 2023Phil HitModified title
126642view18:02, 8 June 2023Thanos Oikonomou
126629view15:37, 7 June 2023Uday as
126628view15:35, 7 June 2023Phil HitModified title
126627view15:34, 7 June 2023Phil HitModified title
126626view15:33, 7 June 2023Phil HitNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ACANGeneProductENSG00000157766 (Ensembl)
AGCProteinIPR000961 (InterPro)
AKT1GeneProductENSG00000142208 (Ensembl)
AKT2GeneProductENSG00000105221 (Ensembl)
AKT3GeneProductENSG00000117020 (Ensembl)
ARNTProteinP27540 (Uniprot-TrEMBL)
CCN2GeneProductENSG00000118523 (Ensembl)
CEBPBProteinP17676 (Uniprot-TrEMBL)
CNMDProteinO75829 (Uniprot-TrEMBL) chondromodulin
COL10A1GeneProductENSG00000123500 (Ensembl)
COL1A1GeneProductENSG00000108821 (Ensembl)
COL2A1GeneProductENSG00000139219 (Ensembl)
COL3A1GeneProductENSG00000168542 (Ensembl)
DDR2ProteinQ16832 (Uniprot-TrEMBL)
DIO2GeneProductENSG00000211448 (Ensembl)
EPAS1GeneProductENSG00000116016 (Ensembl) AKA HIF2A
Endothelial cell proliferationPathwayWikiData Identifier: Q14860496
FGF23ProteinENSG00000118972 (Ensembl)
FGFR1ProteinP11362 (Uniprot-TrEMBL)
FGFR2ProteinP21802 (Uniprot-TrEMBL)
FGFR3ProteinP22607 (Uniprot-TrEMBL)
FGFR4ProteinP22455 (Uniprot-TrEMBL)
FOSBGeneProductENSG00000125740 (Ensembl)
FOSGeneProductENSG00000170345 (Ensembl)
FOSL1GeneProductENSG00000175592 (Ensembl)
FOSL2GeneProductENSG00000075426 (Ensembl)
GANCGeneProductENSG00000214013 (Ensembl)
HIF1AGeneProductENSG00000100644 (Ensembl)
HypertrophyPathwayWikiData Identifier: Q216211
HypoxiaPathwayWikiData Identifier: Q105688
IBSPGeneProductENSG00000029559 (Ensembl)
JAK2GeneProductENSG00000096968 (Ensembl)
JUNBGeneProductENSG00000171223 (Ensembl)
JUNDGeneProductENSG00000130522 (Ensembl)
JUNGeneProductENSG00000177606 (Ensembl)
KDRGeneProductENSG00000128052 (Ensembl)
L-thyroxineMetaboliteCHEBI:18332 (ChEBI)
LAMTOR1ProteinQ6IAA8 (Uniprot-TrEMBL)
MAPK1GeneProductENSG00000100030 (Ensembl)
MAPK3GeneProductENSG00000102882 (Ensembl)
MMP13GeneProductENSG00000137745 (Ensembl)
MigrationPathway
NFKB1GeneProductENSG00000109320 (Ensembl)
NGFGeneProductENSG00000134259 (Ensembl)
NTRK1ProteinP04629 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PIK3CAGeneProductENSG00000121879 (Ensembl)
PRKCAGeneProductENSG00000154229 (Ensembl)
Prolyl 4-hydroxylaseProteinQ9NXG6 (Uniprot-TrEMBL)
RASProteinPF00071 (Pfam)
RELAGeneProductENSG00000173039 (Ensembl)
RELBGeneProductENSG00000104856 (Ensembl)
RUNX2GeneProductENSG00000124813 (Ensembl)
SOX9GeneProductENSG00000125398 (Ensembl)
SPP1GeneProductSPP1 (HGNC)
STAT3GeneProductENSG00000168610 (Ensembl)
TriiodothyronineMetaboliteCHEBI:18258 (ChEBI)
Tube formationPathway
VEGFAGeneProductENSG00000112715 (Ensembl)
VHLProteinP40337 (Uniprot-TrEMBL)
VascularizationPathway

Annotated Interactions

No annotated interactions

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