Osteoarthritic chondrocyte hypertrophy (WP5373)

Homo sapiens

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).


Philip Hittmeyer , Uday Abu Shehab , Athanasios Oikonomou , Denise Slenter , and Eric Weitz


last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.


Homo sapiens



Cell Type Ontology

hypertrophic chondrocyte chondrocyte

Pathway Ontology

hypoxia inducible factor pathway mitogen activated protein kinase signaling pathway fibroblast growth factor signaling pathway thyroid hormone biosynthetic pathway

Disease Ontology



Label Type Compact URI Comment
L-thyroxine Metabolite chebi:18332
O2 Metabolite chebi:15379
Triiodothyronine Metabolite chebi:18258
DIO2 GeneProduct ensembl:ENSG00000211448
RUNX2 GeneProduct ensembl:ENSG00000124813
EPAS1 GeneProduct ensembl:ENSG00000116016 AKA HIF2A
COL10A1 GeneProduct ensembl:ENSG00000123500
MMP13 GeneProduct ensembl:ENSG00000137745
JUND GeneProduct ensembl:ENSG00000130522
COL3A1 GeneProduct ensembl:ENSG00000168542
JUNB GeneProduct ensembl:ENSG00000171223
KDR GeneProduct ensembl:ENSG00000128052
RELA GeneProduct ensembl:ENSG00000173039
FOS GeneProduct ensembl:ENSG00000170345
COL10A1 GeneProduct ensembl:ENSG00000123500
PRKCA GeneProduct ensembl:ENSG00000154229
JUN GeneProduct ensembl:ENSG00000177606
NFKB1 GeneProduct ensembl:ENSG00000109320
COL1A1 GeneProduct ensembl:ENSG00000108821
STAT3 GeneProduct ensembl:ENSG00000168610
JAK2 GeneProduct ensembl:ENSG00000096968
FOSL2 GeneProduct ensembl:ENSG00000075426
HIF1A GeneProduct ensembl:ENSG00000100644
IBSP GeneProduct ensembl:ENSG00000029559
RELB GeneProduct ensembl:ENSG00000104856
MAPK3 GeneProduct ensembl:ENSG00000102882
MAPK1 GeneProduct ensembl:ENSG00000100030
FOSL1 GeneProduct ensembl:ENSG00000175592
NGF GeneProduct ensembl:ENSG00000134259
CCN2 GeneProduct ensembl:ENSG00000118523
SPP1 GeneProduct hgnc.symbol:SPP1
COL2A1 GeneProduct ensembl:ENSG00000139219
FOSB GeneProduct ensembl:ENSG00000125740
VEGFA GeneProduct ensembl:ENSG00000112715
VEGFA GeneProduct ensembl:ENSG00000112715
RUNX2 GeneProduct ensembl:ENSG00000124813
NGF GeneProduct ensembl:ENSG00000134259
PIK3CA GeneProduct ensembl:ENSG00000121879
MAPK1 GeneProduct ensembl:ENSG00000100030
MAPK3 GeneProduct ensembl:ENSG00000102882
AKT1 GeneProduct ensembl:ENSG00000142208
AKT2 GeneProduct ensembl:ENSG00000105221
AKT3 GeneProduct ensembl:ENSG00000117020
COL10A1 GeneProduct ensembl:ENSG00000123500
VEGFA GeneProduct ensembl:ENSG00000112715
MMP13 GeneProduct ensembl:ENSG00000137745
SOX9 GeneProduct ensembl:ENSG00000125398
COL2A1 GeneProduct ensembl:ENSG00000139219
GANC GeneProduct ensembl:ENSG00000214013
COL2A1 GeneProduct ensembl:ENSG00000139219
ACAN GeneProduct ensembl:ENSG00000157766
VEGFA GeneProduct ensembl:ENSG00000112715
HIF1A GeneProduct ensembl:ENSG00000100644
HIF1A GeneProduct ensembl:ENSG00000100644
HIF1A GeneProduct ensembl:ENSG00000100644
HIF1A GeneProduct ensembl:ENSG00000100644
HIF1A GeneProduct ensembl:ENSG00000100644
CNMD Protein uniprot:O75829 chondromodulin
CEBPB Protein uniprot:P17676 Transcription factor
CEBPB Protein uniprot:P17676
DDR2 Protein uniprot:Q16832
FGFR1 Protein uniprot:P11362
FGF23 Protein ensembl:ENSG00000118972
FGFR2 Protein uniprot:P21802
FGFR3 Protein uniprot:P22607
FGFR4 Protein uniprot:P22455
LAMTOR1 Protein uniprot:Q6IAA8
NTRK1 Protein uniprot:P04629
RAS Protein pfam:PF00071
AGC Protein interpro:IPR000961
ARNT Protein uniprot:P27540
Prolyl 4-hydroxylase Protein uniprot:Q9NXG6
VHL Protein uniprot:P40337
ARNT Protein uniprot:P27540
ARNT Protein uniprot:P27540


  1. Regulation of distinct biological activities of the NF-kappaB transcription factor complex by acetylation. Chen LF, Greene WC. J Mol Med (Berl). 2003 Sep;81(9):549–57. PubMed Europe PMC Scholia
  2. Hypoxia-responsive transcription factors. Cummins EP, Taylor CT. Pflugers Arch. 2005 Sep;450(6):363–71. PubMed Europe PMC Scholia
  3. Involvement of SOX-9 and FGF-23 in RUNX-2 regulation in osteoarthritic chondrocytes. Orfanidou T, Iliopoulos D, Malizos KN, Tsezou A. J Cell Mol Med. 2009 Sep;13(9B):3186–94. PubMed Europe PMC Scholia
  4. Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba S, et al. Nat Med. 2010 Jun;16(6):678–86. PubMed Europe PMC Scholia
  5. Matrix metalloproteinase 13 loss associated with impaired extracellular matrix remodeling disrupts chondrocyte differentiation by concerted effects on multiple regulatory factors. Borzí RM, Olivotto E, Pagani S, Vitellozzi R, Neri S, Battistelli M, et al. Arthritis Rheum. 2010 Aug;62(8):2370–81. PubMed Europe PMC Scholia
  6. C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes. Hirata M, Kugimiya F, Fukai A, Saito T, Yano F, Ikeda T, et al. Hum Mol Genet. 2012 Mar 1;21(5):1111–23. PubMed Europe PMC Scholia
  7. Hypoxia-driven pathways in bone development, regeneration and disease. Maes C, Carmeliet G, Schipani E. Nat Rev Rheumatol. 2012 Mar 27;8(6):358–66. PubMed Europe PMC Scholia
  8. Fibroblast growth factor 23 and Klotho are present in the growth plate. Raimann A, Ertl DA, Helmreich M, Sagmeister S, Egerbacher M, Haeusler G. Connect Tissue Res. 2013;54(2):108–17. PubMed Europe PMC Scholia
  9. Deiodinase 2 upregulation demonstrated in osteoarthritis patients cartilage causes cartilage destruction in tissue-specific transgenic rats. Nagase H, Nagasawa Y, Tachida Y, Sakakibara S, Okutsu J, Suematsu N, et al. Osteoarthritis Cartilage. 2013 Mar;21(3):514–23. PubMed Europe PMC Scholia
  10. Hypoxia promotes redifferentiation and suppresses markers of hypertrophy and degeneration in both healthy and osteoarthritic chondrocytes. Markway BD, Cho H, Johnstone B. Arthritis Res Ther. 2013 Aug 21;15(4):R92. PubMed Europe PMC Scholia
  11. Consequences of chondrocyte hypertrophy on osteoarthritic cartilage: potential effect on angiogenesis. Pesesse L, Sanchez C, Delcour JP, Bellahcène A, Baudouin C, Msika P, et al. Osteoarthritis Cartilage. 2013 Dec;21(12):1913–23. PubMed Europe PMC Scholia
  12. Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis. Bomer N, den Hollander W, Ramos YFM, Bos SD, van der Breggen R, Lakenberg N, et al. Ann Rheum Dis. 2015 Aug;74(8):1571–9. PubMed Europe PMC Scholia
  13. Conditional Deletion of Fgfr3 in Chondrocytes leads to Osteoarthritis-like Defects in Temporomandibular Joint of Adult Mice. Zhou S, Xie Y, Li W, Huang J, Wang Z, Tang J, et al. Sci Rep. 2016 Apr 4;6:24039. PubMed Europe PMC Scholia
  14. Fibroblast Growth Factor 23 drives MMP13 expression in human osteoarthritic chondrocytes in a Klotho-independent manner. Bianchi A, Guibert M, Cailotto F, Gasser A, Presle N, Mainard D, et al. Osteoarthritis Cartilage. 2016 Nov;24(11):1961–9. PubMed Europe PMC Scholia
  15. Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis. Ripmeester EGJ, Timur UT, Caron MMJ, Welting TJM. Front Bioeng Biotechnol. 2018 Mar 19;6:18. PubMed Europe PMC Scholia