PMID- 20404338
OWN - NLM
STAT- MEDLINE
DCOM- 20100810
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 27
DP  - 2010 Jul 2
TI  - Inhibition of hypoxia-inducible factor-targeting prolyl hydroxylase 
      domain-containing protein 2 (PHD2) enhances matrix synthesis by human 
      chondrocytes.
PG  - 20472-80
LID - 10.1074/jbc.M110.115238 [doi]
AB  - Human articular cartilage is an avascular tissue, and therefore it functions in a 
      hypoxic environment. Cartilage cells, the chondrocytes, have adapted to this and 
      actually use hypoxia to drive tissue-specific functions. We have previously shown 
      that human chondrocytes enhance cartilage matrix synthesis in response to hypoxia 
      specifically through hypoxia-inducible factor 2alpha (HIF-2alpha)-mediated 
      up-regulation of master regulator transcription factor SOX9, which in turn drives 
      expression of the main cartilage-specific extracellular matrix genes. HIF-alpha 
      isoforms are themselves regulated by specific prolyl hydroxylase 
      domain-containing proteins, which target them for proteosomal degradation. In 
      fact, prolyl hydroxylase domains are the direct oxygen sensors because they 
      require molecular oxygen as a co-substrate. Here, we have identified PHD2 as the 
      dominant isoenzyme regulating HIF-2alpha stability in human chondrocytes. 
      Moreover, specific inhibition of PHD2 using RNA interference-mediated depletion 
      caused an up-regulation of SOX9 and enhanced extracellular matrix protein 
      production. Depletion of PHD2 resulted in greater HIF-2alpha levels and therefore 
      enhanced SOX9-induced cartilage matrix production compared with the levels 
      normally found in hypoxia (1% oxygen) implying that PHD2 inhibition offers a 
      novel means to enhance cartilage repair in vivo. The need for HIF-specific 
      hydroxylase inhibition was highlighted because treatment with the 2-oxoglutarate 
      analogue dimethyloxalylglycine (which also inhibits the collagen prolyl 
      4-hydroxylases) prevented secretion of type II collagen, a critical cartilage 
      matrix component.
FAU - Thoms, Brendan L
AU  - Thoms BL
AD  - From The Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College 
      London, 65 Aspenlea Road, London W6 8LH, United Kingdom.
FAU - Murphy, Christopher L
AU  - Murphy CL
LA  - eng
PT  - Journal Article
DEP - 20100419
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Isoenzymes)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (SOX9 Transcription Factor)
RN  - 0 (SOX9 protein, human)
RN  - 9007-34-5 (Collagen)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Base Sequence
MH  - Cartilage, Articular/cytology/physiology
MH  - Cells, Cultured
MH  - Child
MH  - Chondrocytes/cytology/*physiology
MH  - Collagen/metabolism
MH  - Extracellular Matrix/*physiology
MH  - Female
MH  - Gene Deletion
MH  - Humans
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases
MH  - Isoenzymes/genetics
MH  - Male
MH  - Middle Aged
MH  - Procollagen-Proline Dioxygenase/*antagonists & inhibitors/genetics
MH  - RNA, Small Interfering/genetics
MH  - SOX9 Transcription Factor/genetics
MH  - Transcription, Genetic
MH  - Transfection
PMC - PMC2898297
EDAT- 2010/04/21 06:00
MHDA- 2010/08/11 06:00
PMCR- 2011/07/02
CRDT- 2010/04/21 06:00
PHST- 2010/04/21 06:00 [entrez]
PHST- 2010/04/21 06:00 [pubmed]
PHST- 2010/08/11 06:00 [medline]
PHST- 2011/07/02 00:00 [pmc-release]
AID - S0021-9258(20)57330-4 [pii]
AID - M110.115238 [pii]
AID - 10.1074/jbc.M110.115238 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Jul 2;285(27):20472-80. doi: 10.1074/jbc.M110.115238. Epub 2010 
      Apr 19.