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Interference with cellular differentiation by D-serine through antagonism at N-methyl-D-aspartate receptors composed of NR1 and NR3A subunits in chondrocytes.
J Cell Physiol. 2009 Sep; 220(3):756-64.JC

Abstract

Serine racemase (SR) is responsible for the biosynthesis of D-serine (D-Ser), an endogenous co-agonist for the glycine (Gly)-binding site on N-methyl-D-aspartate (NMDA) receptors, from L-Ser in the brain. We have previously demonstrated high expression of SR by chondrocytes in cartilage. In this study, we attempted to elucidate the possible functional role of D-Ser in chondrogenesis. Expression of mRNA and corresponding protein was seen for SR in cultured rat costal chondrocytes, while the addition of L-Ser significantly increased intracellular and extracellular levels of D-Ser. In organotypic cultured mouse embryonic metatarsals isolated before vascularization, SR mRNA was highly localized in hypertrophic and calcified chondrocytes. Exposure to D-Ser not only suppressed several chondrocytic maturation markers, including alkaline phosphatase (ALP) activity, Ca2+ accumulation, nodule formation, and osteopontin expression, in rat chondrocytes, but also delayed chondral mineralization in mouse metatarsals. Either NMDA or Gly alone significantly increased Ca2+ accumulation in cultured chondrocytes, whereas D-Ser significantly prevented Ca2+ accumulation by Gly, but not by NMDA. Gly alone also significantly increased gene transactivation by the introduction of runt-related transcription factor-2 (Runx2) in COS7 cells transfected with NR1 and NR3A subunits, while D-Ser significantly prevented the increase by Gly without affecting the promoter activity of Runx2. In both cultured chondrocytes and metatarsals from NR1-null mice, significant decreases were seen in ALP activity and chondral mineralization, respectively. These results suggest that D-Ser may negatively regulate cellular differentiation through inhibiting NMDA receptors composed of NR1 and NR3A subunits in a manner related to Runx2 transcriptional activity in chondrocytes.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Takarada T
Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa 920-1192, Japan.
Takahata Y
No affiliation info available
Iemata M
No affiliation info available
Hinoi E
No affiliation info available
Uno K
No affiliation info available
Hirai T
No affiliation info available
Yamamoto T
No affiliation info available
Yoneda Y
No affiliation info available

MeSH

Alkaline PhosphataseAnimalsAnimals, NewbornCOS CellsCalcification, PhysiologicCalciumCell DifferentiationChlorocebus aethiopsChondrocytesChondrogenesisCore Binding Factor Alpha 1 SubunitFemaleGene Expression Regulation, DevelopmentalGene Expression Regulation, EnzymologicGestational AgeGlycineHumansMembrane GlycoproteinsMetatarsal BonesMiceMice, KnockoutN-MethylaspartateOsteopontinRNA, MessengerRacemases and EpimerasesRatsRats, WistarReceptors, N-Methyl-D-AspartateSerineTime FactorsTissue Culture TechniquesTransfection

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19452450

Citation

Takarada, Takeshi, et al. "Interference With Cellular Differentiation By D-serine Through Antagonism at N-methyl-D-aspartate Receptors Composed of NR1 and NR3A Subunits in Chondrocytes." Journal of Cellular Physiology, vol. 220, no. 3, 2009, pp. 756-64.
Takarada T, Takahata Y, Iemata M, et al. Interference with cellular differentiation by D-serine through antagonism at N-methyl-D-aspartate receptors composed of NR1 and NR3A subunits in chondrocytes. J Cell Physiol. 2009;220(3):756-64.
Takarada, T., Takahata, Y., Iemata, M., Hinoi, E., Uno, K., Hirai, T., Yamamoto, T., & Yoneda, Y. (2009). Interference with cellular differentiation by D-serine through antagonism at N-methyl-D-aspartate receptors composed of NR1 and NR3A subunits in chondrocytes. Journal of Cellular Physiology, 220(3), 756-64. https://doi.org/10.1002/jcp.21821
Takarada T, et al. Interference With Cellular Differentiation By D-serine Through Antagonism at N-methyl-D-aspartate Receptors Composed of NR1 and NR3A Subunits in Chondrocytes. J Cell Physiol. 2009;220(3):756-64. PubMed PMID: 19452450.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interference with cellular differentiation by D-serine through antagonism at N-methyl-D-aspartate receptors composed of NR1 and NR3A subunits in chondrocytes. AU - Takarada,Takeshi, AU - Takahata,Yoshifumi, AU - Iemata,Mika, AU - Hinoi,Eiichi, AU - Uno,Kyosuke, AU - Hirai,Takao, AU - Yamamoto,Tomomi, AU - Yoneda,Yukio, PY - 2009/5/20/entrez PY - 2009/5/20/pubmed PY - 2009/7/17/medline SP - 756 EP - 64 JF - Journal of cellular physiology JO - J Cell Physiol VL - 220 IS - 3 N2 - Serine racemase (SR) is responsible for the biosynthesis of D-serine (D-Ser), an endogenous co-agonist for the glycine (Gly)-binding site on N-methyl-D-aspartate (NMDA) receptors, from L-Ser in the brain. We have previously demonstrated high expression of SR by chondrocytes in cartilage. In this study, we attempted to elucidate the possible functional role of D-Ser in chondrogenesis. Expression of mRNA and corresponding protein was seen for SR in cultured rat costal chondrocytes, while the addition of L-Ser significantly increased intracellular and extracellular levels of D-Ser. In organotypic cultured mouse embryonic metatarsals isolated before vascularization, SR mRNA was highly localized in hypertrophic and calcified chondrocytes. Exposure to D-Ser not only suppressed several chondrocytic maturation markers, including alkaline phosphatase (ALP) activity, Ca2+ accumulation, nodule formation, and osteopontin expression, in rat chondrocytes, but also delayed chondral mineralization in mouse metatarsals. Either NMDA or Gly alone significantly increased Ca2+ accumulation in cultured chondrocytes, whereas D-Ser significantly prevented Ca2+ accumulation by Gly, but not by NMDA. Gly alone also significantly increased gene transactivation by the introduction of runt-related transcription factor-2 (Runx2) in COS7 cells transfected with NR1 and NR3A subunits, while D-Ser significantly prevented the increase by Gly without affecting the promoter activity of Runx2. In both cultured chondrocytes and metatarsals from NR1-null mice, significant decreases were seen in ALP activity and chondral mineralization, respectively. These results suggest that D-Ser may negatively regulate cellular differentiation through inhibiting NMDA receptors composed of NR1 and NR3A subunits in a manner related to Runx2 transcriptional activity in chondrocytes. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/19452450/Interference_with_cellular_differentiation_by_D_serine_through_antagonism_at_N_methyl_D_aspartate_receptors_composed_of_NR1_and_NR3A_subunits_in_chondrocytes_ L2 - https://doi.org/10.1002/jcp.21821 DB - PRIME DP - Unbound Medicine ER -