Differential Stimulation of Prostaglandin G/H Synthase-2 in Osteocytes and Other Osteogenic Cells by Pulsating Fluid Flow

Westbroek, Irene; Ajubi, N.E.; Alblas, M.J.; Semeins, Cornelis M.; Klein‐Nulend, Jenneke; Burgér, E.H.; Nijweide, Peter J.

doi:10.1006/bbrc.2000.2154

Cited by 106 publications

(88 citation statements)

References 39 publications

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“…It has become clear that exposure of osteoblasts and osteocytes to fluid flow in vitro results in activation of signaling pathways known to play an essential role in bone metabolism in vivo. [6][7][8][9][10][11] These results have been found in osteoblastic cell lines, and in primary bone cells from several species including humans. 8,[12][13][14][15][16][17][18][19] Specifically, the production of nitric oxide (NO) and prostaglandins (PG) is stimulated in bone cells in response to fluid flow.…”

Section: Introductionsupporting

confidence: 52%

Release of nitric oxide, but not prostaglandin E₂, by bone cells depends on fluid flow frequency

Mullender

Dijcks

Bacabac

et al. 2006

Journal Orthopaedic Research

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Loading frequency is an important parameter for the stimulation of bone formation in vivo. It is still unclear how the information of external loading characteristics is conveyed to osteoblasts and osteoclasts. Osteocytes are thought to detect mechanical loads by sensing fluid flow through the lacuno-canalicular network within bone and to translate this information into chemical signals. The signaling molecules nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) are known to play important roles in the adaptive response of bone to mechanical loads. We have investigated the effects of fluid flow frequency on the production of PGE 2 and NO in bone cells in vitro. Pulsatile fluid flow with different frequencies stimulated the release of NO by MC3T3-E1 osteoblasts in a dosedependent manner. In contrast, PGE 2 production was enhanced consistently by all fluid flow regimes, independent of flow frequency. This implies that the NO response may play a role in mediating the differential effects of the various loading patterns on bone. ß

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Section: Introductionsupporting

confidence: 52%

Release of nitric oxide, but not prostaglandin E₂, by bone cells depends on fluid flow frequency

Mullender

Dijcks

Bacabac

et al. 2006

Journal Orthopaedic Research

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“…These mechanical signals could adaptively change functions of bone-forming cells (osteocytes and osteoblasts). The results of extensive in vivo and in vitro studies indicated that these mechanical signals induced the expression of COX-2, an inducible isoform of prostaglandin G/H synthase, via a complexity of signal transduction systems (15,26,(35)(36)(37). However, little is known about the mechanism that regulates cox-2 transcription in response to mechanical stress.…”

Section: Discussionmentioning

confidence: 99%

Fluid Shear Stress-induced Cyclooxygenase-2 Expression Is Mediated by C/EBP β, cAMP-response Element-binding Protein, and AP-1 in Osteoblastic MC3T3-E1 Cells

Ogasawara

Arakawa

Kaneda

et al. 2001

Journal of Biological Chemistry

145

104

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Mechanical loading is crucial for maintenance of bone integrity and architecture, and prostaglandins are an important mediator of mechanosensing. Cyclooxygenase-2 (COX-2), an inducible isoform of prostaglandin G/H synthase, is induced by mechanical loading-derived fluid shear stress in bone-forming cells such as osteoblasts and osteocytes. In this study, we investigated transcription factor and transcriptional regulatory elements responsible for the shear stress-induced COX-2 expression in osteoblastic MC3T3-E1 cells. When the cells were transfected with luciferase-reporter plasmids including the 5-flanking region of the murine cox-2 gene, the fluid shear stress increased the luciferase activities, consistent with the induction of COX-2 mRNA and protein expression. Deletion analysis of the promoter region revealed that the shear stress-induced luciferase responses were regulated by two regions, ؊172 to ؊100 base pair (bp) and ؊79 to ؊46 bp, of the cox-2 promoter, in which putative cis-elements of C/EBP ␤, AP-1, cAMP-response element-binding protein (CREB), and E box are included. Mutation of sites of C/EBP ␤, AP-1, and/or cAMP-response element decreased the shear stress-induced luciferase activities, whereas mutation of the E box did not affect the responses. In an electrophoretic mobility shift assay, shear stress enhanced nuclear extract binding to double-stranded oligonucleotide probes containing C/EBP ␤ and AP-1-binding motifs, and the bands of the complexes were supershifted by the addition of antibody specific for each regulator. Although the binding activity of CREB toward its probe was unaffected by shear stress, the phosphorylation of CREB was enhanced by the stress. These data suggest that C/EBP ␤, AP-1, and CREB play crucial roles in the shear stress-induced cox-2 expression in osteoblasts.Mechanical loading applied to the skeleton is crucial to the development and maintenance of bone integrity and architecture. A decrease in the mechanical loading due to prolonged immobilization or weightlessness in space reduces the bone formation rate, resulting in bone loss (1-3). On the other hand, an increase in mechanical loading causes a gain in bone density (4, 5). Thus, bone tissue is sensitive to mechanical stimulation. Mechanical loading on bone generates extracellular matrix deformation and fluid flow, and the mechanical stimuli are translated to mechanical signals such as mechanical strain and fluid shear stress, respectively (6). Evidence obtained from in vitro studies indicates that osteocytes embedded in the lacunae/ canaliculi system and osteoblasts and bone cells lining the bone surface are mechanosensors that detect load-derived mechanical stimuli (7,8). By these bone-forming cells, the mechanical stimuli are translated into cellular signaling factors.Mechanical stress induces the expressions of several kinds of proteins in bone-forming cells such as insulin-like growth factor-I and -II, transforming growth factor-␤, osteocalcin, osteopontin, c-Fos, nitric-oxide synthase, and cyclooxygenase-2 (COX-...

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“…11 Furthermore, osteocytes are more responsive to fluid flow shear stress than to other forms of mechanical strain, such as substrate stretching. [12][13][14] As demonstrated, substrate stretching results in an increase of collagen or bone matrix synthesis. Indeed, bone mass and formation is increased with dynamic loading, while bone resorption is decreased.…”

Section: The Effect Of Mechanical Strain On Soft (Cardiovascular) Andmentioning

confidence: 99%

The effect of mechanical strain on soft (cardiovascular) and hard (bone) tissues

Boccafoschi

Mosca

Ramella

et al. 2013

Cell Adhesion & Migration

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Differential Stimulation of Prostaglandin G/H Synthase-2 in Osteocytes and Other Osteogenic Cells by Pulsating Fluid Flow

Cited by 106 publications

References 39 publications

Release of nitric oxide, but not prostaglandin E₂, by bone cells depends on fluid flow frequency

Release of nitric oxide, but not prostaglandin E₂, by bone cells depends on fluid flow frequency

Fluid Shear Stress-induced Cyclooxygenase-2 Expression Is Mediated by C/EBP β, cAMP-response Element-binding Protein, and AP-1 in Osteoblastic MC3T3-E1 Cells

The effect of mechanical strain on soft (cardiovascular) and hard (bone) tissues

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Differential Stimulation of Prostaglandin G/H Synthase-2 in Osteocytes and Other Osteogenic Cells by Pulsating Fluid Flow

Cited by 106 publications

References 39 publications

Release of nitric oxide, but not prostaglandin E2, by bone cells depends on fluid flow frequency

Release of nitric oxide, but not prostaglandin E2, by bone cells depends on fluid flow frequency

Fluid Shear Stress-induced Cyclooxygenase-2 Expression Is Mediated by C/EBP β, cAMP-response Element-binding Protein, and AP-1 in Osteoblastic MC3T3-E1 Cells

The effect of mechanical strain on soft (cardiovascular) and hard (bone) tissues

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Release of nitric oxide, but not prostaglandin E₂, by bone cells depends on fluid flow frequency

Release of nitric oxide, but not prostaglandin E₂, by bone cells depends on fluid flow frequency