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Glutamate transporter inhibitors influence osteoblast gene expression and activity

Brakspear, Karen Sarah, Parsons, P. and Mason, Deborah Jane 2009. Glutamate transporter inhibitors influence osteoblast gene expression and activity. International Journal of Experimental Pathology 90 (2) , A107-A108. 10.1111/j.1365-2613.2008.00644.x

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Introduction Mechanical loading plays a key role in the physiology of bone, allowing functional adaption to its environment. A screen for genes associated with mechanical load-induced osteogenic signalling identified the glutamate transporter GLAST-1, implicating the excitatory amino acid glutamate in the mechanoresponse. Five high affinity Na+- dependant excitatory amino acid transporters (EAATs) terminate glutamatergic signalling. EAAT1 (GLAST-1) is expressed by osteocytes and bone-forming osteoblasts in vivo. Materials and Methods We inhibited glutamate transport in osteosarcoma cell lines and primary osteoblasts using small molecule inhibitors of EAATs 1-5 [L-trans-Pyrrolidine-2,4- dicarboxylic acid (t-PDC) and DL-threo-b-benzyloxyaspartic acid (TBOA)]. These inhibitors (0-1 mM) were toxic at high concentrations and had no effect on proliferation over 5 days, but did influence gene expression determined by quantitative RT-PCR and alkaline phosphatase activity. Results RT-PCR revealed mRNA expression of EAATs 1-3 and both splice variants of EAAT1 (EAAT1a and EAAT1exon9s kip) in MG-63 and SaOS-2 osteoblasts. To our knowledge, this is the first reported observation of expression of the EAAT1ex9skip variant in bone cells. In MG-63 osteoblasts, osteocalcin and osteonectin expression were significantly upregulated upon EAAT inhibition by t-PDC in the presence of glutamate and also by TBOA alone over 24 h; whereas no changes in expression were detected upon treatment with glutamate alone. In primary osteoblasts, long-term exposure to high levels of glutamate increased osteocalcin expression and down-regulated EAAT1. TBOA significantly upregulated alkaline phosphatase activity in SaOS-2 and primary osteoblasts. Discussion This data confirms previously published data that mechanically regulated glutamate transporters may be important in regulating bone homeostasis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QR Microbiology
Publisher: Wiley-Blackwell
ISSN: 0959-9673
Last Modified: 18 Sep 2017 10:14

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