Expression of an N-Methyl-D-Aspartate-Type Receptor by Human and Rat Osteoblasts and Osteoclasts Suggests a Novel Glutamate Signaling Pathway in Bone

Patton, Amanda J.; Genever, Paul G.; Birch, Mark; Suva, Larry J.; Skerry, Timothy M.

doi:10.1016/s8756-3282(98)00061-1

Cited by 164 publications

(102 citation statements)

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“…Our finding that NMDAR-2C is expressed in rat osteoblasts, where the influence of mGluR activation is inhibitory, is in accord with this idea. NMDAR-2D is also known to be expressed in bone cells (11).…”

Section: Discussionmentioning

confidence: 99%

“…There is believed to be "cross-talk" between the different glutamate receptor subtypes, primarily by mGluRs acting to regulate activity of iGluRs (20). To date, only iGluRs, primarily the NMDA-type, have been detected in bone cells (10,11).The first electrophysiological study of the action of glutamate on bone-derived cells used the human osteoblast-like MG-63 cell line. Bath-applied L-glutamate and NMDA had very similar effects on these cells, with both agonists markedly increasing membrane conductance (21).…”

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confidence: 99%

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Expression of Functional Metabotropic Glutamate Receptors in Primary Cultured Rat Osteoblasts

Gu¹,

Publicover

2000

Journal of Biological Chemistry

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Osteoblasts and osteoclasts express functional N-methyl-D-aspartate (NMDA) receptors, which participate in regulation of bone matrix. In rat femoral osteoblasts held in whole cell clamp there is a robust NMDA current but little if any response to L- It is well established that bone cells are regulated in their activity both by circulating hormones (1) and by the interacting effects of a number of locally acting intercellular signals, including prostaglandins, growth factors, cytokines, and nitric oxide (2-9). Recently, it has been reported that functional NMDA 1 -type glutamate receptors are expressed in a number of bone cell types, including rat and human osteoblasts and osteoclasts, MG-63 osteosarcoma cells, and in bone marrow megakaryocytes (10 -15). Osteoblasts, which contain high levels of glutamate (16), express regulatory proteins required for vesicular exocytosis that co-localize with glutamate (17). In vitro, osteoblasts secrete glutamate in a regulated manner. 2Initial histochemical data show that nerve endings able to secrete L-glutamate may also occur within bone (16). Antagonists of NMDA receptors modulate the activities of both osteoblasts and osteoclasts, the bone cells responsible for deposition and resorbtion of bone matrix (10, 14, 18). These findings suggest that glutamate-mediated signaling occurs in bone, in a manner analogous to glutamatergic transmission between neurons, and that it contributes to regulation of bone matrix (19).The NMDA receptor is part of a complex glutamatergic system in the central nervous system, comprising several receptor types. Glutamate receptors can be divided into iGluRs (including the NMDA type found in bone) and mGluRs. mGluRs are G-protein-linked receptors that stimulate PLC (group 1 mGluRs) or inhibit adenyl cyclase (group 2 and group 3 mGluRs) (20). There is believed to be "cross-talk" between the different glutamate receptor subtypes, primarily by mGluRs acting to regulate activity of iGluRs (20). To date, only iGluRs, primarily the NMDA-type, have been detected in bone cells (10,11).The first electrophysiological study of the action of glutamate on bone-derived cells used the human osteoblast-like MG-63 cell line. Bath-applied L-glutamate and NMDA had very similar effects on these cells, with both agonists markedly increasing membrane conductance (21). However, during our studies on NMDA-induced currents in femoral explant-derived osteoblasts of rat (15), we made the surprising observation that the responses to NMDA and L-glutamate differed markedly. Cells that showed a well developed response to bath-applied NMDA gave only a very small current upon application of L-glutamate. This finding suggests the expression in femoral osteoblasts of a second type of glutamate receptor, which negatively modulates the NMDA receptor/channel. We have therefore looked for mGluRs in rat femoral osteoblasts and examined the effects of their activation on osteoblastic NMDA receptor/channels. We report that mGluR-1b receptors are expressed in these cells, that their activatio...

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Section: Discussionmentioning

confidence: 99%

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Expression of Functional Metabotropic Glutamate Receptors in Primary Cultured Rat Osteoblasts

Gu¹,

Publicover

2000

Journal of Biological Chemistry

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“…This neuropeptide was shown to stimulate (16) or inhibit (17) bone resorption depending on the experimental conditions and to regulate intercellular coupling of osteoblasts (18). The glutamate/aspartate transporter (GLAST) was identified in osteoblasts and osteocytes (19), as was a glutamate receptor in osteoblasts and osteoclasts (20).In this study, we report the presence of another regulatory system in bone, primarily known as a neural system. To gain better insight into the properties of osteocytes, we have used suppression subtractive hybridization (21).…”

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confidence: 86%

Expression of Serotonin Receptors in Bone

Westbroek¹,

Plas²,

Rooij³

et al. 2001

Journal of Biological Chemistry

191

138

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The 5-hydroxytryptamine (5-HT) receptors 5-HT 2A , 5-HT 2B , and 5-HT 2C belong to a subfamily of serotonin receptors. Amino acid and mRNA sequences of these receptors have been published for several species including man. The 5-HT 2 receptors have been reported to act on nervous, muscle, and endothelial tissues. Here we report the presence of 5-HT 2B receptor in fetal chicken bone cells. 5-HT 2B receptor mRNA expression was demonstrated in osteocytes, osteoblasts, and periosteal fibroblasts, a population containing osteoblast precursor cells. Pharmacological studies using several agonists and antagonists showed that occupancy of the 5-HT 2B receptor stimulates the proliferation of periosteal fibroblasts. Activity of the 5-HT 2A receptor could however not be excluded. mRNA for both receptors was shown to be equally present in adult mouse osteoblasts. Osteocytes, which showed the highest expression of 5-HT 2B receptor mRNA in chicken, and to a lesser extent osteoblasts, are considered to be mechanosensor cells involved in the adaptation of bone to its mechanical usage. Nitric oxide is one of the signaling molecules that is released upon mechanical stimulation of osteocytes and osteoblasts. The serotonin analog ␣-methyl-5-HT, which preferentially binds to 5-HT 2 receptors, decreased nitric oxide release by mechanically stimulated mouse osteoblasts. These results demonstrate that serotonin is involved in bone metabolism and its mechanoregulation.The main highly differentiated cell types in bone tissue are the osteoclast, the osteoblast (OB), 1 and the osteocyte (OCY). Osteoclasts are multinucleated cells of hemopoietic origin and are related to the monocyte/macrophage (1, 2, 3). Osteoblasts on the other hand are of mesenchymal stock. Their stem and progenitor cells are present in the periosteum, endosteum, and bone marrow stroma (4). Osteocytes differentiate from osteoblasts. During the process of bone formation, a number of cells from the osteoblast layer is encapsulated in the newly formed bone matrix, whereas the other cells retract with the bone formation front. The cells that are incorporated in the bone matrix change from a cuboidal into a more stellate-shaped morphology and become osteocytes. The result of this process is a three-dimensional cellular network of osteocytes within the mineralized matrix connected to each other and to the bone surface cells by thin cell processes (5).Together these three cell types produce, maintain, and adapt or repair, if necessary, the mineralized bone matrix. Osteoclasts are capable of bone resorption, osteoblasts of bone formation. The function of osteocytes is less well understood. Because of their location within the bone matrix, osteocytes are in a prime position for the detection of mechanical inadequacies of the tissue. They are believed to act as sensor cells that translate mechanical stimuli resulting from gravitational and muscular forces on the skeleton into biochemical signals. These biochemical signals in turn activate the effectors of bone turnover, osteoclasts...

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“…43 The expression of NMDA receptors in human and rat osteoblasts and osteoclasts suggests a role of glutamate in bone cells signalling. 47 Immunohistochemical evidence also demonstrated glutamate-containing nerves in bone. 48 Moreover, using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) techniques, NMDAR1 and NMDAR2A subunits of NMDA receptors are both expressed in normal and OA chondrocytes.…”

Section: Discussionmentioning

confidence: 96%

Hyaluronic acid attenuates osteoarthritis development in the anterior cruciate ligament‐transected knee: Association with excitatory amino acid release in the joint dialysate

Jean

Wen

Chang

et al. 2006

Journal Orthopaedic Research

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We previously reported increased release of the excitatory amino acid (EAA) neurotransmitters, glutamate and aspartate, during the early stage of experimental osteoarthritis (OA). Our present objective was to study the effect of intraarticular injection of hyaluronic acid (HA) on OA development, and to analyze concomitant changes in EAA levels in dialysates of anterior cruciate ligament-transected (ACLT) knee joints. OA was induced in Wistar rats by ACLT of one hindlimb; the knee of the other hindlimb was used as the sham-operated control. HA group (n ¼ 12) were injected intraarticularly in the ACLT knee with 1 mg of HA once a week for 5 consecutive weeks, starting at 8 weeks after surgery. Saline group (n ¼ 12) were injected as above with normal saline. The sham-operated group, underwent arthrotomy, but not ACLT, and received no treatment (n ¼ 14). Twenty weeks after surgery, knee joint dialysates were collected by microdialysis and EAA levels assayed by high-performance liquid chromatography, and gross morphological examination and histopathological evaluation were performed on the medial femoral condyles and synovia. Rats receiving intraarticular HA injections showed a significantly lower degree of cartilage degeneration on the medial femoral condyle at both the macroscopic level and on the Mankin grading scale than rats receiving saline injections. Intraarticular HA treatment also suppressed synovitis. Moreover, glutamate and aspartate levels were significantly reduced in the HA group compared to the saline group. Intraarticular injection of HA limits articular cartilage and synovium damage and OA formation, and, in parallel, reduces EAA levels in ACLT joint dialysates. This study suggests that the underlying mechanism of the anti-inflammatory effect of HA is to inhibit glutamate and aspartate release in ACLT knee joints, which attenuates the early development of OA. ß

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Expression of an N-Methyl-D-Aspartate-Type Receptor by Human and Rat Osteoblasts and Osteoclasts Suggests a Novel Glutamate Signaling Pathway in Bone

Cited by 164 publications

References 20 publications

Expression of Functional Metabotropic Glutamate Receptors in Primary Cultured Rat Osteoblasts

Expression of Functional Metabotropic Glutamate Receptors in Primary Cultured Rat Osteoblasts

Expression of Serotonin Receptors in Bone

Hyaluronic acid attenuates osteoarthritis development in the anterior cruciate ligament‐transected knee: Association with excitatory amino acid release in the joint dialysate

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