Bone histomorphometric and biomechanical abnormalities in mice homozygous for deletion of the dopamine transporter gene

Bliziotes, Michael; McLoughlin, S. W.; Gunness, M.; Fumagalli, Fabio; Jones, Sara R.; Caron, Marc G.

doi:10.1016/s8756-3282(99)00232-x

Cited by 67 publications

(36 citation statements)

References 25 publications

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“…[18]. These studies, combined with the results presented here, suggest that neurotransmitters, through their respective transporters and receptors, may play a significant but underappreciated role as signaling molecules that modulate skeletal health.…”

Section: Discussionsupporting

confidence: 56%

“…In osteoblast and osteocyte cells, expression and regulation of the excitatory amino acid glutamate/aspartate transporter (GLAST) by mechanical loading has been described [4]. We have demonstrated that disruption of the dopamine transporter (DAT) gene in mice [18] results in deficiencies in skeletal structure and integrity. More recently, we have analyzed skeletal structure in mice with disruption of the serotonin transporter gene (5-HTT −/− mice) [19].…”

Section: Introductionmentioning

confidence: 99%

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Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells

Bliziotes

Eshleman

Burt‐Pichat

et al. 2006

Bone

113

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells

Bliziotes

Eshleman

Burt‐Pichat

et al. 2006

Bone

113

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“…Furthermore, a leptindependent regulation of bone mass by the central nervous system has been demonstrated in mice, which appears to be mediated by sympathetic innervation (Ducy et al, 2000;Takeda et al, 2002). The role of sympathetic innervation in bone remodeling is also supported by the changes in bone mass observed in mice deficient in genes coding for dopamine ␤-hydroxylase, dopamine transporter, and Y2 receptors (Bliziotes et al, 2000;Baldock et al, 2002;Takeda et al, 2002).…”

Section: Introductionmentioning

confidence: 94%

Expression of Semaphorin‐3A and its receptors in endochondral ossification: Potential role in skeletal development and innervation

Gomez

Burt‐Pichat

Malléin-Gerin

et al. 2005

Developmental Dynamics

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Bone tissue is densely innervated, and there is increasing evidence for a neural control of bone metabolism. Semaphorin-3A is a very important regulator of neuronal targeting in the peripheral nervous system as well as in angiogenesis, and knockout of the Semaphorin-3A gene induces abnormal bone and cartilage development. We analyzed the spatial and temporal expression patterns of Semaphorin-3A signaling molecules during endochondral ossification, in parallel with the establishment of innervation. We show that osteoblasts and chondrocytes differentiated in vitro express most members of the Semaphorin-3A signaling system (Semaphorin-3A, Neuropilin-1, and Plexins-A1 and -A2). In vitro, osteoclasts express most receptor chains but not the ligand. In situ, these molecules are all expressed in the periosteum and by resting, prehypertrophic and hypertrophic chondrocytes in ossification centers before the onset of neurovascular invasion. They are detected later in osteoblasts and also osteoclasts, with differences in intensity and regional distribution. Semaphorin-3A and Neuropilin-1 are also expressed in the bone marrow. Plexin-A3 is not expressed by bone cell lineages in vitro. It is detected early in the periosteum and hypertrophic chondrocytes. After the onset of ossification, this chain is restricted to a network of cell processes in close vicinity to the cells lining the trabeculae, similar to the pattern observed for neural markers at the same stages. After birth, while the density of innervation decreases, Plexin-A3 is strongly expressed by blood vessels on the ossification front. In conclusion, Semaphorin-3A signaling is present in bone and seems to precede or coincide at the temporal but also spatial level with the invasion of bone by blood vessels and nerve fibers. Expression patterns suggest Plexin-A3/Neuropilin-1 as a candidate receptor in target cells for the regulation of bone innervation by Semaphorin-3A. Developmental Dynamics 234:393-403, 2005.

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“…Indeed, dopamine transporter (Dat)-deficient mice display a low bone mass phenotype [68,69], however the mechanism whereby dopamine reuptake affects bone mass is unclear so far. On the other hand, rats treated with serotonin have increased BMD [70] and lack of the serotonin transporter (5-HTT) [71] or serotonin receptor (5-HTR) [72] in mice induces a low bone mass phenotype due to a decrease in bone formation.…”

Section: More Complexity To Comementioning

confidence: 99%

Regulation of bone remodeling by the central and peripheral nervous system

Elefteriou

2008

Archives of Biochemistry and Biophysics

205

150

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The homeostatic nature of bone remodeling has become a notion further supported lately by the demonstration that neuropeptides and their receptors regulate osteoblast and osteoclast function in vivo. Following initial studies reporting the presence of nerves and nerve-derived products within the bone micro-environment and the expression of receptors for these neuropeptides in bone cells, new experimental and mechanistic evidence based on in vivo murine genetic and pharmacologic models recently demonstrated that inputs from the central and peripheral nervous system feed into the already complex regulatory machinery controlling bone remodeling. The function of a number of "osteo-neuromediators" has been characterized, including norepinephrine and the beta 2-adrenergic receptor, Neuropeptide Y and the Y1 and Y2 receptors, endocannabinoids and the CB1 and CB2 receptors, as well as dopamine, serotonin and their receptors and transporters, Calcitonin gene-related peptide, and neuronal NOS. This new body of evidence suggests that neurons in the central nervous system integrate clues from the internal and external milieux, such as energy homeostasis, glycemia or reproductive signals, with the regulation of bone remodeling. The next major tasks in this new area of bone biology will be to understand, at the molecular level, the mechanisms by which common central neural systems regulate and integrate these major physiological functions, the relative importance of the central and peripheral actions of neuropeptides present in both compartments and their relationship, and how bone cells signal back to central centers, because the definition of a homeostatic function implies the existence of feedback signals. Together, these findings shed a new light on the complexity of the mechanisms regulating bone remodeling and uncovered new potential therapeutic strategies for the design of bone anabolic treatments. This review summarizes the latest advances in this area, focusing on investigations based on in vivo animal studies. KeywordsBone; osteoblast; osteoclast; neuron; sympathetic nervous system; hypothalamus; leptin; neuropeptide; adrenergic receptor; neuropeptide Y; endocannabinoid The central nervous system restrains bone formationIt is the association between body weight and bone density as well as the association between loss of gonadal function and osteoporosis that initially pointed to the putative existence of a common factor regulating body weight, reproduction and bone mass. Based on the knowledge that the adipocyte-derived hormone leptin regulates major physiological functions, including body weight and reproduction, via the hypothalamus and its receptor ObRb, it was

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Bone histomorphometric and biomechanical abnormalities in mice homozygous for deletion of the dopamine transporter gene

Cited by 67 publications

References 25 publications

Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells

Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells

Expression of Semaphorin‐3A and its receptors in endochondral ossification: Potential role in skeletal development and innervation

Regulation of bone remodeling by the central and peripheral nervous system

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