Evidence for targeted vesicular glutamate exocytosis in osteoblasts

Bhangu, P.S.; Genever, Paul G.; Spencer, Gary J.; Grewal, T. S.; Skerry, Timothy M.

doi:10.1016/s8756-3282(01)00482-3

Cited by 76 publications

(56 citation statements)

References 44 publications

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“…Moreover, the presence of the regulatory proteins required for vesicular exocytosis has been shown in a number of osteosarcoma cell lines and in primary osteoblasts (29). This suggested the possibility that ATP could be released (or coreleased with glutamate) by a mechanism of regulated secretion.…”

Section: Resultsmentioning

confidence: 97%

Mechanically Induced ATP Release from Human Osteoblastic Cells

Romanello

Pani

Bicego

et al. 2001

Biochemical and Biophysical Research Communications

156

131

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Section: Resultsmentioning

confidence: 97%

Mechanically Induced ATP Release from Human Osteoblastic Cells

Romanello

Pani

Bicego

et al. 2001

Biochemical and Biophysical Research Communications

156

131

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“…In contrast, glutamate signals in vivo are likely to be spatially restricted and dynamically regulated. Previous work demonstrated that glutamate is released from megakaryocytes52 and osteoblasts 53. We did not repeat these experiments but acknowledge that further testing of glutamate release would be of interest, in particular in the native bone marrow environment.…”

Section: Discussionmentioning

confidence: 95%

N‐methyl‐d‐aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines

Kamal

Green

Hearn

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Intracellular calcium pathways regulate megakaryopoiesis but details are unclear.We examined effects of NMDAR‐mediated calcium influx on normal and leukemic cells in culture.NMDARs facilitated differentiation of normal but proliferation of leukemic megakaryocytes.NMDAR inhibitors induced differentiation of leukemic Meg‐01 cells. Background N‐methyl‐d‐aspartate receptors (NMDARs) contribute calcium influx in megakaryocytic cells but their roles remain unclear; both pro‐ and anti‐differentiating effects have been shown in different contexts.ObjectivesThe aim of this study was to clarify NMDAR contribution to megakaryocytic differentiation in both normal and leukemic cells.MethodsMeg‐01, Set‐2, and K‐562 leukemic cell lines were differentiated using phorbol‐12‐myristate‐13‐acetate (PMA, 10 nmol L−1) or valproic acid (VPA, 500 μmol L−1). Normal megakaryocytes were grown from mouse marrow‐derived hematopoietic progenitors (lineage‐negative and CD41a‐enriched) in the presence of thrombopoietin (30‐40 nmol L−1). Marrow explants were used to monitor proplatelet formation in the native bone marrow milieu. In all culture systems, NMDARs were inhibited using memantine and MK‐801 (100 μmol L−1); their effects compared against appropriate controls.ResultsThe most striking observation from our studies was that NMDAR antagonists markedly inhibited proplatelet formation in all primary cultures employed. Proplatelets were either absent (in the presence of memantine) or short, broad and intertwined (with MK‐801). Earlier steps of megakaryocytic differentiation (acquisition of CD41a and nuclear ploidy) were maintained, albeit reduced. In contrast, in leukemic Meg‐01 cells, NMDAR antagonists inhibited differentiation in the presence of PMA and VPA but induced differentiation when applied by themselves.Conclusions NMDAR‐mediated calcium influx is required for normal megakaryocytic differentiation, in particular proplatelet formation. However, in leukemic cells, the main NMDAR role is to inhibit differentiation, suggesting diversion of NMDAR activity to support leukemia growth. Further elucidation of the NMDAR and calcium pathways in megakaryocytic cells may suggest novel ways to modulate abnormal megakaryopoiesis.

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“…Glutamate is critical for the differentiation of osteoblasts [34] and osteoclasts [35], and is intimately involved in the mature functions of both cell types [36,37]. Furthermore, glutamate has been demonstrated to be secreted by osteoclasts [36] and activated osteoblasts [38][39][40], and there is evidence implicating glutamate signalling mechanisms in primary bone cancer pathophysiology [41]. However, the relevance of glutamate in bone metastasis has not yet been examined, and this is the first study to hypothesize that glutamate released from non-CNS cancer cells invading bone may be specifically disruptive to normal bone signalling mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Cancer cell lines release glutamate into the extracellular environment

Seidlitz

Sharma

Saikali

et al. 2009

Clin Exp Metastasis

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Bone is one of the most frequent sites for metastasis of breast and prostate cancers. Bone metastases are associated with pathologic changes in bone turnover and severe pain. The mechanisms that trigger these effects are not well understood, but it is postulated that tumour cells release factors which interfere with signalling processes critical to bone homeostasis. We have identified that several cancer cell lines known to cause bone disruption in animal models of bone metastasis appear to secrete glutamate into their extracellular environment in vitro. Although these cells also express specific glutamate receptors, the implications of this potentially disruptive chemical signal are discussed in relation to normal glutamate-dependent communication processes in bone and a possible mechanistic connection is made between tumour cell glutamate release and the development of pathological changes in bone turnover.

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Evidence for targeted vesicular glutamate exocytosis in osteoblasts

Cited by 76 publications

References 44 publications

Mechanically Induced ATP Release from Human Osteoblastic Cells

Mechanically Induced ATP Release from Human Osteoblastic Cells

N‐methyl‐d‐aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines

Cancer cell lines release glutamate into the extracellular environment

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