PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling

Li, Tian-Fang; Zuscik, Michael J.; Ionescu, Andreia; Zhang, Xiaopeng; Rosier, Randy N.; Schwarz, Edward M.; Drissi, Hicham; O’Keefe, Regis J.

doi:10.1016/j.yexcr.2004.06.019

Cited by 80 publications

(69 citation statements)

References 58 publications

(62 reference statements)

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“…Although it remains currently unclear why BMP-2 treatment increases the NS398 responsiveness of hypertrophic markers, it is possible that a negative feedback effect of exogenous BMP-2 on endogenous BMP-2 levels renders hypertrophic differentiation more susceptible to COX-2 inhibition. In contrast to the here reported anti-hypertrophic effect of COX-2 inhibition, PGE 2 has been demonstrated to delay (BMP-2 induced) hypertrophic differentiation via PKA and PKC signalling (Li et al, 2004;Clark et al, 2009). These confl icting results may be related to the choice of experimental models: whereas we used chondroprogenitors, PKA/PKC involvement was tested in mature chondrocyte cultures.…”

Section: Cox-2 -Integration Into Known Chondrogenic Signallingmentioning

confidence: 60%

Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification

Welting

Caron²,

Emans

et al. 2011

eCM

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Skeletogenesis and bone fracture healing involve endochondral ossification, a process during which cartilaginous primordia are gradually replaced by bone tissue. In line with a role for cyclooxygenase-2 (COX-2) in the endochondral ossifi cation process, non-steroidal anti-inflammatory drugs (NSAIDs) were reported to negatively affect bone fracture healing due to impaired osteogenesis. However, a role for COX-2 activity in the chondrogenic phase of endochondral ossifi cation has not been addressed before. We show that COX-2 activity fulfi ls an important regulatory function in chondrocyte hypertrophic differentiation. Our data reveal essential cross-talk between COX-2 and bone morphogenic protein-2 (BMP-2) during chondrocyte hypertrophic differentiation. BMP-2 mediated chondrocyte hypertrophy is associated with increased COX-2 expression and pharmacological inhibition of COX-2 activity by NSAIDs (e.g., Celecoxib) decreases hypertrophic differentiation in various chondrogenic models in vitro and in vivo, while leaving early chondrogenic development unaltered. Our fi ndings demonstrate that COX-2 activity is a novel factor partaking in chondrocyte hypertrophy in the context of endochondral ossifi cation and these observations provide a novel etiological perspective on the adverse effects of NSAIDs on bone fracture healing and have important implications for the use of NSAIDs during endochondral skeletal development.

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Section: Cox-2 -Integration Into Known Chondrogenic Signallingmentioning

confidence: 60%

Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification

Welting

Caron²,

Emans

et al. 2011

eCM

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“…Thus, impairment of the AA cascade with a subsequent decrease in PGE 2 release could be necessary to complete Caco-2 differentiation, or at least to complete the development of the epithelial barrier function characteristic of differentiated Caco-2 cultures. In this way, Li et al (45) observed that PGE 2 inhibits the expression of differentiation-related genes and regulates chondrocyte maturation.…”

Section: Discussionmentioning

confidence: 97%

Arachidonic acid cascade and epithelial barrier function during Caco-2 cell differentiation

Martín‐Venegas

Roig-Pérez

Ferrer

2006

Journal of Lipid Research

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The small intestinal epithelium is a highly dynamic system continuously renewed by a process involving cell proliferation and differentiation. The intestinal epithelium constitutes a permeability barrier regulating the vectorial transport of ions, water, and solutes. Morphological changes during cell differentiation, as well as changes in the activity of brush-border enzymes and the expression of transport proteins, are well established. However, little is known about the arachidonic acid (AA) cascade underlying epithelial cell differentiation or its role in the development of epithelial barrier function. The main purpose of this study was to examine the activity of the high-molecular-weight phospholipases A 2 (PLA 2 ) and cyclooxygenase (COX) pathway during differentiation, with particular emphasis on paracellular permeability. PLA 2 activity, AA release, COX-2 expression, prostaglandin E 2 (PGE 2 ) production, and paracellular permeability were studied in preconfluent, confluent, and differentiated Caco-2 cell cultures. Our results show that Caco-2 differentiation induces a decrease in both calcium-independent PLA 2 activity and COX-2 expression and, consequently, a decrease in AA release and PGE 2 synthesis in parallel with a reduction in paracellular permeability. Moreover, the addition of PGE 2 to differentiated cells, at concentrations similar to those detected in nondifferentiated cultures, induces the disruption of epithelial barrier function. These results suggest that AA release by calcium-independent PLA 2 , COX-2 expression, and subsequent PGE 2 release are important for the maintenance of paracellular permeability in differentiated Caco-2 cells.-Martín-Venegas, R., S. RoigPérez, R. Ferrer, and J. J. Moreno. Arachidonic acid cascade and epithelial barrier function during Caco-2 cell differentiation.

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“…Alternatively, alteration of phosphorylation on the axoneme may be occurring. Crosstalk and regulation of signaling by PKA and PKC occur in many cell types in either a synergistic or antagonistic fashion [53][54][55][56][57]. It is possible that the phosphorylation of a target protein on the axoneme by PKA produces a conformation in which a phosphorylation target of PKC is masked.…”

Section: Discussionmentioning

confidence: 99%

Differential in Vivo Effects of Whole Cigarette Smoke Exposure Versus Cigarette Smoke Extract on Mouse Ciliated Tracheal Epithelium

Elliott

Sisson

West

et al. 2006

Experimental Lung Research

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In this study the authors compared the affect of vapor phase cigarette smoke (CS) versus cigarette smoke extract (CSE) on the lungs and upper airway of C57BL/6 mice. The authors found that CSE treatment significantly increased neutrophil influx (P < .001), baseline ciliary beat frequency (CBF) (P < .05), and protein kinase C activity compared to CS and controls. Isoproterenol increased CBF with CS exposure, but decreased CBF with CSE (P < .01). Isoproterenol increased protein kinase A (PKA) activity in all groups except CSE. CSE exposure induced inflammatory cell bronchiolitis. These data indicate that CSE exposure has differential effects on the lungs and tracheal epithelium compared to CS exposure.Ciliary motility provides the driving force for mucociliary clearance. Normal function of the airway mucociliary clearance system prevents the attachment and colonization of pulmonary pathogens in the upper airways. Mucociliary dysfunction caused by impaired ciliary motility results in mucus accumulation, airway obstruction, and bacterial colonization, increasing the likelihood of infection in the lower airway [1][2][3]. Mucociliary clearance is affected by exposure to a number of environmental agents [4,5], including cigarette smoke. Exposure to cigarette smoke (CS) has been linked to the development of lung cancer, emphysema, chronic bronchitis, and chronic obstructive pulmonary disease (COPD) [6]. Smokers are at a higher risk for pulmonary infection [7]. Chronic exposure to tobacco smoke is associated with increased ciliary abnormality [8] and reduced mucociliary clearance [9]. The increased risk for infection seen in smokers may be due to alterations in ciliary function in the upper airway.Several studies have revealed that ciliary activity is controlled by phosphorylation of axonemal proteins [10][11][12]. Protein kinase C (PKC) and cyclic adenosine monophosphate (CAMP)-Address correspondence to Todd A. Wyatt, PhD, University of Nebraska Medical Center, 985300 Nebraska Medical Center, Omaha, NE 68198-5300, USA. E-mail: twyatt@unmc.edu. NIH Public Access Author ManuscriptExp Lung Res. Author manuscript; available in PMC 2007 November 21. Published in final edited form as:Exp Lung Res. 2006 ; 32(3-4): 99-118. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript dependent protein kinase (PKA) are important regulators of airway ciliary beat frequency (CBF). Agents that increase PKC are associated with decreased CBF [13][14][15]. Alternatively, agents associated with increased CBF also increase PKA activity [16]. In past studies, we have shown that exposure of ciliated epithelial cells to cigarette smoke extract (CSE) in culture and whole cigarette smoke in vivo induces an increase in epithelial cell PKC activity [15,[17][18][19]. Many animal models of exposure to cigarette smoke components exist. Most recently, Miller and colleagues have developed a method of exposure consisting of intranasal administration of CSE [20]. This method was shown to induce an inflammatory response similar to ...

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PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling

Cited by 80 publications

References 58 publications

Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification

Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification

Arachidonic acid cascade and epithelial barrier function during Caco-2 cell differentiation

Differential in Vivo Effects of Whole Cigarette Smoke Exposure Versus Cigarette Smoke Extract on Mouse Ciliated Tracheal Epithelium

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