Genetic Analysis of Lrp5 Function in Osteoblast Progenitors

Yadav, Vijay K.; Arantes, Henrique Pierotti; Barros, Elizabete Ribeiro; Lazaretti-Castro, Marise; Ducy, Patricia

doi:10.1007/s00223-010-9350-7

Cited by 30 publications

(26 citation statements)

References 30 publications

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“…As a consequence, serum levels of serotonin were increased in Lrp5 knock-out homozygous and heterozygous mice. Their findings are in agreement with numerous clinical observations in OPPG and HBM patients [45-47] and suggest that altered LRP5 functionality may be acting on bone at a distance by regulating circulating levels of serotonin, which would then bind to specific receptors on bone cells, and not directly by controlling Wnt signaling in bone cells, as commonly maintained (Figure 1). Strikingly, ex vivo experiments revealed that 50 mM 5-HT could indeed stop osteoblast proliferation by binding to the HTR1B receptor and activating PKA and CREB transcription factor [44], although previous independent results showed that lower (0.1 mM) doses of serotonin could enhance the proliferation of human primary osteoblasts in vitro [48], suggesting a possible dose-dependent effect.…”

Section: The Wnt Connectionsupporting

confidence: 90%

Serotonin: a novel bone mass controller may have implications for alveolar bone

Galli

Macaluso

Passeri

2013

J Negat Results BioMed

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As recent studies highlight the importance of alternative mechanisms in the control of bone turnover, new therapeutic approaches can be envisaged for bone diseases and periodontitis-induced bone loss. Recently, it has been shown that Fluoxetine and Venlafaxine, serotonin re-uptake inhibitors commonly used as antidepressants, can positively or negatively affect bone loss in rat models of induced periodontitis. Serotonin is a neurotransmitter that can be found within specific nuclei of the central nervous system, but can also be produced in the gut and be sequestered inside platelet granules. Although it is known to be mainly involved in the control of mood, sleep, and intestinal physiology, recent evidence has pointed at far reaching effects on bone metabolism, as a mediator of the effects of Lrp5, a membrane receptor commonly associated with Wnt canonical signaling and osteoblast differentiation. Deletion of Lrp5 in mice lead to increased expression of Tryptophan Hydroxylase 1, the gut isoform of the enzyme required for serotonin synthesis, thus increasing serum levels of serotonin. Serotonin, in turn, could bind to HTR1B receptors on osteoblasts and stop their proliferation by activating PKA and CREB.Although different groups have reported controversial results on the existence of an Lrp5-serotonin axis and the action of serotonin in bone remodeling, there is convincing evidence that serotonin modulators such as SSRIs can affect bone turnover. Consequently, the effects of this drug family on periodontal physiology should be thoroughly explored.

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Section: The Wnt Connectionsupporting

confidence: 90%

Serotonin: a novel bone mass controller may have implications for alveolar bone

Galli

Macaluso

Passeri

2013

J Negat Results BioMed

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“…The potential stage specificity of LRP5 function was addressed by two different groups but with conflicting results. Whereas one group reported that deletion of Lrp5, either in mature osteoblasts (ColI-Cre) 8 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a008334 (Yadav et al 2008) or in mesenchymal progenitors (Dermo1-Cre, and therefore all cells of the osteoblast lineage) (Yadav et al 2010), did not produce any bone phenotype, a second group showed that deletion of Lrp5 predominantly in osteocytes (differentiated from osteoblasts; Dmp1-Cre) 9 resulted in less bone (Cui et al 2011). The different findings support competing models.…”

Section: Wnt Proteinsmentioning

confidence: 99%

Development of the Endochondral Skeleton

Long

Ornitz

2013

Cold Spring Harbor Perspectives in Biology

521

493

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SUMMARYMuch of the mammalian skeleton is composed of bones that originate from cartilage templates through endochondral ossification. Elucidating the mechanisms that control endochondral bone development is critical for understanding human skeletal diseases, injury response, and aging. Mouse genetic studies in the past 15 years have provided unprecedented insights about molecules regulating chondrocyte formation, chondrocyte maturation, and osteoblast differentiation, all key processes of endochondral bone development. These include the roles of the secreted proteins IHH, PTHrP, BMPs, WNTs, and FGFs, their receptors, and transcription factors such as SOX9, RUNX2, and OSX, in regulating chondrocyte and osteoblast biology. This review aims to integrate the known functions of extracellular signals and transcription factors that regulate development of the endochondral skeleton.

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“…Subsequently, osteogenesis is induced through differentiation of mesenchymal cells into osteoblasts and suppression of osteoblasts apoptosis, and concomitantly, bone resorption is suppressed through inhibition of osteoclast differentiation (15,16). Recently, mutated LRP-5 has been identified as the causative gene for osteoporosis-pseudoglioma syndrome (OPPG), and has been found to be involved in bone metabolism-related disease (3,36). Moreover, inhibition of DKK-1, an LRP-5 inhibitory factor, or SFRP-1 and SFRP-2, the Wnt inhibitory factors, results in enhanced osteogenesis (26,34).…”

Section: Discussionmentioning

confidence: 99%

Periosteum-derived cells respond to mechanical stretch and activate Wnt andBMP signaling pathways

et al. 2014

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The periosteum supplies osteoblasts and nutrients for bone metabolism and is important for osteoblast differentiation and osteogenesis. Recently, periosteum-derived cells have been used for orofacial bone regeneration therapy. However, little is known about the function of the periosteum in physiological bone remodeling. On our hypothesis that the periosteum senses a mechanical stress to induce bone remodeling, we subjected human jaw bone periosteum cells (HJBPCs) to uniaxial stretching for 24 h and characterized their gene expression profiles by microarray analysis. Of 62,976 genes detected, 550 genes related to bone metabolism were extracted, and 76 of these genes with large changes in gene expression were short-listed. The results indicated that mechanical stretch in HJBPCs regulated the expression levels of genes involved in the Wingless-type MMTV integration (Wnt) site, bone morphogenetic protein (BMP) signaling pathways, and inflammatory cytokines. We propose that periosteum-derived cells sense mechanical stress and then activate and regulate signals for osteoblast differentiation and osteogenesis.

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Genetic Analysis of Lrp5 Function in Osteoblast Progenitors

Cited by 30 publications

References 30 publications

Serotonin: a novel bone mass controller may have implications for alveolar bone

Serotonin: a novel bone mass controller may have implications for alveolar bone

Development of the Endochondral Skeleton

Periosteum-derived cells respond to mechanical stretch and activate Wnt andBMP signaling pathways

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