Glutamate receptor agonists and glutamate transporter antagonists regulate differentiation of osteoblast lineage cells
Open accessAbstract
Development and function of osteoblast lineage cells are regulated by a complex microenvironment consisting of the bone extracellular matrix, cells, systemic hormones and cytokines, autocrine and paracrine factors, and mechanical load. Apart from receptors that transduce extracellular signals into the cell, molecular transporters play a crucial role in the cellular response to the microenvironment. Transporter molecules are responsible for cellular uptake of nutritional components, elimination of metabolites, ion transport, and cell-cell communication. In this report, the expression of molecular transporters in osteoblast lineage cells was investigated to assess their roles in cell development and activity. Low-density arrays, covering membrane and vesicular transport molecules, were used to assess gene expression in osteoblasts representing early and late differentiation states. Receptors and transporters for the amino acid glutamate were found to be differentially expressed during osteoblast development. Glutamate is a neurotransmitter in the central nervous system, and the mechanisms of its release, signal transduction, and cellular reabsorption in the synaptic cleft are well understood. Less clear, however, is the control of equivalent processes in peripheral tissues. In primary osteoblasts, inhibition of glutamate transporters with nonselective inhibitors leads to an increase in the concentration of extracellular glutamate. This change was accompanied by a decrease in osteoblast proliferation, stimulation of alkaline phosphatase, and the expression of transcripts encoding osteocalcin. Enzymatic removal of extracellular glutamate abolished these pro-differentiation effects, as did the inhibition of PKC- and Erk1/2-signaling pathways. These findings demonstrate that glutamate signaling promotes differentiation and activation of osteoblast lineage cells. Consequently, the glutamate system may represent a putative therapeutic target to induce an anabolic response in the skeletal system. Known antagonists of glutamate transporters will serve as lead compounds in developing new and specific bioactive molecules.
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Bone is innervated by glutamatergic fibers and glutamate receptors are thought to play a role in osteoblastic differentiation and proliferation.
“Bone is innervated by glutamatergic fibers and glutamate receptors are thought to play a role in osteoblastic differentiation and proliferation (Jones et al., 2004;Xie et al., 2016).”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Xie et al., 2016
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Glutamate receptors in domestication and modern human evolution
O’Rourke, T., & Boeckx, C. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.004 · Cited by 50 · see citing works
- Authors
- Xie, W., Dolder, S., Siegrist, M., Wetterwald, A., & Hofstetter, W.
- Affiliations
- University of Bern (CH)
- Corresponding author
- Hofstetter, Willy
- Venue
- Calcified Tissue International
- Published
- 2016-03-26
- Volume
- 99
- Issue
- 2
- Pages
- 142-154
- ISSN
- 0171-967X (ISSN-L)
- 1432-0827
- OpenAlex
- W2307654109
- Cited by
- 12
- References
- 51
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- green
- boris.unibe.ch
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Calcified Tissue International (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, other-oa)
- Open Access CRIS of the University of Bern
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (NCCR TransCure)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Keywords
- glutamate, glutamate transporters, glutamate receptor agonists, osteogenic differentiation, osteoblast lineage cells, extracellular glutamate, alkaline phosphatase, osteocalcin, osteoblast proliferation, PKC signaling, ERK signaling, bone anabolic therapy, bone matrix
- MeSH terms
- Animals, Bone and Bones, Cell Communication, Cell Differentiation, Cell Line, Glutamates, Mice, Inbred C57BL, Osteoblasts, Osteogenesis, Osteocalcin, Receptors, Glutamate, Excitatory Amino Acid Agonists, Cell Lineage, Amino Acid Transport System X-AG
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