Prostaglandin Promotion of Osteocyte Gap Junction Function through Transcriptional Regulation of Connexin 43 by Glycogen Synthase Kinase 3/β-Catenin Signaling

Xia, Xuan; Batra, Nidhi; Shi, Qian; Bonewald, Lynda F.; Sprague, Eugene A.; Jiang, Jean X.

doi:10.1128/mcb.01844-08

Cited by 122 publications

(100 citation statements)

References 52 publications

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“…PI3K has been reported to mediate activation of integrins after fluid flow in endothelial cells (27)(28)(29), and we demonstrated the activation of PI3K signaling by fluid flow in osteocytes (Fig. S5) (30). Fluid flow-induced Cx43 HC opening, as detected by dye uptake, was inhibited significantly by LY294002, a PI3K signaling inhibitor (Fig.…”

Section: Resultsmentioning

confidence: 65%

Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels

Batra¹,

Burra²,

Siller-Jackson³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The connexin 43 (Cx43) hemichannel (HC) in the mechanosensory osteocytes is a major portal for the release of factors responsible for the anabolic effects of mechanical loading on bone formation and remodeling. However, little is known about how the Cx43 molecule responds to mechanical stimulation leading to the opening of the HC. Here, we demonstrate that integrin α5β1 interacts directly with Cx43 and that this interaction is required for mechanical stimulation-induced opening of the Cx43 HC. Direct mechanical perturbation via magnetic beads or conformational activation of integrin α5β1 leads to the opening of the Cx43 HC, and this role of the integrin is independent of its association with an extracellular fibronectin substrate. PI3K signaling is responsible for the shear stress-induced conformational activation of integrin α5β1 leading to the opening of the HC. These results identify an unconventional function of integrin that acts as a mechanical tether to induce opening of the HC and provide a mechanism connecting the effect of mechanical forces directly to anabolic function of the bone.

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Section: Resultsmentioning

confidence: 65%

Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels

Batra¹,

Burra²,

Siller-Jackson³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

214

205

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“…In osteoblasts, administration of FFSS can induce signaling pathways that stabilize b-catenin and thereby promote the activity of LEF/TCF transcription factors (Xia et al 2010) and/or induce the activity of protein kinase A (Cherian et al 2003). Notably, while culture of epiphyseal chondrocytes under FFSS conditions resulted in increased activation of either TOP-luciferase (a LEF/TCF reporter) (Fig.…”

Section: Ffss Engages a Pka/creb Signaling Pathway To Promote Prg4 Exmentioning

confidence: 99%

Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways

et al. 2014

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Lubricin is a secreted proteoglycan encoded by the Prg4 locus that is abundantly expressed by superficial zone articular chondrocytes and has been noted to both be sensitive to mechanical loading and protect against the development of osteoarthritis. In this study, we document that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion, which correlates with augmented levels of phospho-S133 CREB and increased nuclear localization of CREB-regulated transcriptional coactivators (CRTCs) in this tissue. Furthermore, we found that fluid flow shear stress (FFSS) increases secretion of extracellular PGE2, PTHrP, and ATP (by epiphyseal chondrocytes), which together engage both PKA-and Ca ++ -regulated signaling pathways that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes. Because running and FFSS both boost Prg4 expression in a COX-2-dependent fashion, our results suggest that mechanical motion may induce Prg4 expression in the superficial zone of articular cartilage by engaging the same signaling pathways activated in vitro by FFSS that promote CREB-dependent gene expression in this tissue.

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“…A growing body of work indicates that Wnt signaling is an important regulator of skeletal response to mechanical loading (9,10). Experimental loading regulates the expression of several Wnt ligands, receptors, and antagonists, which in turn increases ␤-catenin nuclear translocation (10 -12) and the expression of its target genes (13)(14)(15).…”

mentioning

confidence: 99%

Hypoxia-inducible Factor-1α Protein Negatively Regulates Load-induced Bone Formation

Riddle

Leslie

Gross

et al. 2011

Journal of Biological Chemistry

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Background:The mechanisms by which bone responds to changes in its loading environment are poorly understood. Results: Mechanical signals induce Hif-1␣ expression, and mice lacking Hif-1␣ in bone are more responsive to loading. Conclusion: Hif-1␣ is a novel regulator of skeletal mechanotransduction that impinges on Wnt signaling. Significance: Understanding skeletal mechanotransduction may lead to the development of therapies designed to enhance bone formation.

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Prostaglandin Promotion of Osteocyte Gap Junction Function through Transcriptional Regulation of Connexin 43 by Glycogen Synthase Kinase 3/β-Catenin Signaling

Cited by 122 publications

References 52 publications

Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels

Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels

Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways

Hypoxia-inducible Factor-1α Protein Negatively Regulates Load-induced Bone Formation

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