Expression of Functional Gap Junctions and Regulation by Fluid Flow in Osteocyte-Like MLO-Y4 Cells

Cheng, Benxu; Zhao, Shujie; Luo, Jian; Sprague, Eugene A.; Bonewald, Lynda F.; Jiang, Jean X.

doi:10.1359/jbmr.2001.16.2.249

Cited by 192 publications

(196 citation statements)

References 45 publications

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“…More importantly, MLO-Y4 cells express an osteocyte-specific marker protein, E11 (21). We and others (20,22,23) have identified Cx43 as a major gap junction protein expressed in MLO-Y4 cells. We have shown that MLO-Y4 cells are functionally coupled and that this coupling is mediated by gap junction channels (23).…”

mentioning

confidence: 74%

Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP2 Receptor

Cherian

Cheng

et al. 2003

Journal of Biological Chemistry

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Fluid flow conditioned medium and PGE 2 stimulated cAMP production and PKA activity suggesting that PGE 2 released by mechanically stimulated cells is responsible for the activation of cAMP and PKA. The adenylate cyclase activators, forskolin and 8-bromo-cAMP, enhanced intercellular connectivity, the number of functional gap junctions, and Cx43 protein expression, whereas the PKA inhibitor, H89, inhibited the stimulatory effect of PGE 2 on gap junctions. These studies suggest that the EP 2 receptor mediates the effects of autocrine PGE 2 on the osteocyte gap junction in response to fluid flow-induced shear stress. These data support the hypothesis that the EP 2 receptor, cAMP, and PKA are critical components of the signaling cascade between mechanical strain and gap junction-mediated communication between osteocytes.

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mentioning

confidence: 74%

Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP2 Receptor

Cherian

Cheng

et al. 2003

Journal of Biological Chemistry

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190

146

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“…Fluid flow-induced shear stress stimulates gap junction-mediated intercellular communication and increases Cx43 expression by the release of prostaglandin (25). PGE 2 in turn functions in an autocrine fashion to activate EP 2 receptor signaling, including increased intracellular cAMP and activated PKA (24).…”

Section: Wnt Signaling In Osteocytes Crosstalk With the Prostaglandimentioning

confidence: 99%

Osteocytes, mechanosensing and Wnt signaling

Bonewald¹,

Johnson²

2008

Bone

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The majority of bone cell biology focuses on activity on the surface of the bone with little attention paid to the activity that occurs below the surface. However, with recent new discoveries, osteocytes, cells embedded within the mineralized matrix of bone, are becoming the target of intensive investigation. In this article, the distinctions between osteoblasts and their descendants, osteocytes, are reviewed. Osteoblasts are defined as cells that make bone matrix and osteocytes are thought to translate mechanical loading into biochemical signals that affect bone (re)modeling. Osteoblasts and osteocytes should have similarities as would be expected of cells of the same lineage, yet these cells also have distinct differences, particularly in their responses to mechanical loading and utilization of the various biochemical pathways to accomplish their respective functions. For example, the Wnt/ β-catenin signaling pathway is now recognized as an important regulator of bone mass and bone cell functions. This pathway is important in osteoblasts for differentiation, proliferation and the synthesis bone matrix, whereas osteocytes appear to use the Wnt/β-catenin pathway to transmit signals of mechanical loading to cells on the bone surface. New emerging evidence suggests that the Wnt/β-catenin pathway in osteocytes may be triggered by crosstalk with the prostaglandin pathway in response to loading which then leads to a decrease in expression of negative regulators of the pathway such as Sost and Dkk1. The study of osteocyte biology is becoming an intense area of research interest and this review will examine some of the recent findings that are reshaping our understanding of bone/bone cell biology. KeywordsOsteocytes; bone; Wnt/β-catenin signaling; Mechanosensation; Mechanical loading Osteocytes compose over 90-95% of all bone cells in the adult skeleton and are thought to respond to mechanical strain to send signals of resorption or formation (70). Osteocytes are usually regularly dispersed throughout the mineralized matrix especially in cortical bone. These cells are connected to each other and cells on the bone surface through dendritic processes that occupy tiny canals called canaliculi (For review see (17)). Not only do these cells communicate with each other and with cells on the bone surface but their dendritic processes are in contact with the bone marrow (59) giving them the potential to recruit osteoclast precursors to stimulate bone resorption (133)(12) and to regulate mesenchymal stem cell differentiation (48).

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“…The most abundant connexin family member present in the skeleton is Cx43 [22][23][24][25][26]. Other connexins are also expressed in bone, specifically Cx45 and Cx46, though their functions in these cells remain unknown [22;23].…”

Section: Connexins In Skeletal Developmentmentioning

confidence: 99%

Cell–cell communication in the osteoblast/osteocyte lineage

Civitelli

2008

Archives of Biochemistry and Biophysics

228

176

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Skeletal development (bone modeling) and its maintenance in post-natal life in response to local and systemic stimuli (bone remodeling) require coordinated activity among osteoblasts (bone forming cells), osteocytes (cells embedded in bone) and osteoclasts (bone resorbing cells), in order to meet the needs of structural integrity, mechanical competence and maintenance of mineral homeostasis. One mechanism of cell-cell interaction is via direct cell-cell communication via gap junctions. These are transmembrane channels that allow continuity of cytoplasms between communicating cells. The biologic importance of connexin43 (Cx43), the most abundant gap junction protein in the skeleton is demonstrated by the skeletal malformations present in oculodentodigital dysplasia (ODDD), a disease linked to Cx43 gene (GJA1) mutations, and by the low bone mass and osteoblast dysfunction in Gja1 ablated mice. The presence of Cx43 is required for osteoblast differentiation and function, and by forming either gap junctions or "hemichannels" Cx43 allows participation of cell networks to responses to extracellular stimuli, via propagation of specific signals converging upon connexin sensitive transcriptional units. Hence, Cx43 is involved in skeletal responsiveness to anabolic signals, as those provided by parathyroid hormone and physical load, the latter function probably involving osteocyte-osteoblast communication.

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Expression of Functional Gap Junctions and Regulation by Fluid Flow in Osteocyte-Like MLO-Y4 Cells

Cited by 192 publications

References 45 publications

Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP2 Receptor

Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP2 Receptor

Osteocytes, mechanosensing and Wnt signaling

Cell–cell communication in the osteoblast/osteocyte lineage

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