Regulation of gene expression and subcellular protein distribution in MLO-Y4 osteocytic cells by lysophosphatidic acid: Relevance to dendrite outgrowth

Waters, Katrina M.; Jacobs, Jon; Gritsenko, Marina; Karin, Norman J.

doi:10.1016/j.bone.2011.02.020

Cited by 13 publications

(11 citation statements)

References 57 publications

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“…In addition, this study demonstrated the dependence on G i to differentiate mature osteoblasts under LPA. Such an effect of LPA on mature osteoblasts is in agreement with its described role in promoting dendrite outgrowth of the osteocyte-like cell line, MLO-Y4 [15,16]. LPA induces changes in the cytoskeleton and stimulates the migration of MC3T3-E1 osteoblastic cells [17].…”

Section: Introductionsupporting

confidence: 74%

Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass

Gennero

Laurencin‐Dalicieux

Conte-Auriol

et al. 2011

Bone

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Lysophosphatidic acid (LPA) is a lipid mediator that acts in paracrine systems via interaction with a subset of G protein-coupled receptors (GPCRs). LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. At least 6 LPA GPCRs have been identified to date: LPA1–LPA6. Several studies have suggested that local production of LPA by tissues and cells contributes to paracrine regulation, and a complex interplay between LPA and its receptors, LPA1 and LPA4, is believed to be involved in the regulation of bone cell activity. In particular, LPA1may activate both osteoblasts and osteoclasts. However, its role has not as yet been examined with regard to the overall status of bone in vivo. We attempted to clarify this role by defining the bone phenotype of LPA1(−/−) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA1 plays an important role in osteogenesis. The LPA1(−/−) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA1 during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA1(−/−) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA1 strongly influences bone development both qualitatively and quantitatively and that, in vivo, its absence results in decreased osteogenesis with no clear modification of osteoclasis. They open perspectives for a better understanding of the role of the LPA/LPA1 paracrine pathway in bone pathophysiology.

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Section: Introductionsupporting

confidence: 74%

Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass

Gennero

Laurencin‐Dalicieux

Conte-Auriol

et al. 2011

Bone

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“…LPA modulates motility in osteoblasts and osteocytes, inducing chemotaxis in murine MC3T3 preosteoblasts 85 and dendrite outgrowth in MLO-Y4 osteoblasts. 86 These findings suggest that LPA may be involved in directing osteoblast migration and morphology during bone remodeling. Recent data provide evidence that osteoclasts produce LPA, which can then act as an additional autocrine signal as well as a paracrine cue to osteoclasts and potentially MSCs.…”

Section: Skeletal Biologymentioning

confidence: 85%

Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering

Binder

Williams

Silva

et al. 2015

Tissue Engineering Part B: Reviews

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The presentation and controlled release of bioactive signals to direct cellular growth and differentiation represents a widely used strategy in tissue engineering. Historically, work in this field has primarily focused on the delivery of large cytokines and growth factors, which can be costly to manufacture and difficult to deliver in a sustained manner. There has been a marked increase over the past decade in the pursuit of lipid mediators due to their wide range of effects over multiple cell types, low cost, and ease of scale-up. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are two bioactive lysophospholipids (LPLs) that have gained attention for use as pharmacological agents in tissue engineering applications. While these lipids can have similar effects on cellular response, they possess distinct chemical backbones, mechanisms of synthesis and degradation, and signaling pathways using a discrete set of G-protein-coupled receptors (GPCRs). LPA and S1P predominantly act extracellularly on their GPCRs and can directly regulate cell survival, differentiation, cytokine secretion, proliferation, and migration-each of the important functions that must be considered in regenerative medicine. In addition to these potent physiological functions, these LPLs play pivotal roles in a number of pathophysiological processes. To capitalize on the promise of these molecules in tissue engineering, these lipids have been incorporated into biomaterials for in vivo delivery. Here, we survey the effects of LPA and S1P on both cellular-and tissue-level phenotypes, with an eye toward regulating stem/progenitor cell growth and differentiation. In particular, we examine work that has translational applications for cell-based tissue engineering strategies in promoting cell survival, bone and cartilage engineering, and therapeutic angiogenesis.

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“…Similarly, 423 gene products were regulated at p<0.1 (Supplementary Table 2). As we have done previously (Waters et al, 2011), we then utilized a fold change cut-off to discern gene products of greatest interest. Table 1 identifies all transcripts significantly fluid flow-regulated by at least ±1.5-fold change at any time point, including 13 at p<0.05 and 22 at p<0.1.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of total RNA was carried out as in Waters, et al (Waters et al, 2011). First, quality was verified using an Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA).…”

Section: Methodsmentioning

confidence: 99%

“…From lists of both significantly regulated gene transcripts (p<0.05) and proteins (p<0.1), an integration network for MLO-Y4 cells exposed to fluid flow was generated using MetaCore pathway analysis software (GeneGo, St. Joseph, MI) as similarly conducted by Waters, et al (Waters et al, 2011). This integration network was developed using the Analyze network algorithm in which root nodes were established from microarray data in conjunction with proteomic data, and additional neighboring nodes and edges established connectivity.…”

Section: Methodsmentioning

confidence: 99%

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Integrative transcriptomic and proteomic analysis of osteocytic cells exposed to fluid flow reveals novel mechano-sensitive signaling pathways

Govey

Jacobs

Tilton

et al. 2014

Journal of Biomechanics

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Osteocytes, positioned within bone's porous structure, are subject to interstitial fluid flow upon whole bone loading. Such fluid flow is widely theorized to be a mechanical signal transduced by osteocytes, initiating a poorly understood cascade of signaling events mediating bone adaptation to mechanical load. The objective of this study was to examine the time course of flow-induced changes in osteocyte gene transcript and protein levels using high-throughput approaches. Osteocyte-like MLO-Y4 cells were subjected to 2 hours of oscillating fluid flow (1 Pa peak shear stress) and analyzed following 0, 2, 8, and 24 hours post-flow incubation. Transcriptomic microarray analysis, followed by gene ontology pathway analysis, demonstrated fluid flow regulation of genes consistent with both known and unknown metabolic and inflammatory responses in bone. Additionally, two of the more highly up-regulated gene products—chemokines Cxcl1 and Cxcl2, supported by qPCR—have not previously been reported as responsive to fluid flow. Proteomic analysis demonstrated greatest up-regulation of the ATP-producing enzyme NDK, calcium-binding Calcyclin, and G protein-coupled receptor kinase 6. Finally, an integrative pathway analysis merging fold changes in transcript and protein levels predicted signaling nodes not directly detected at the sampled time points, including transcription factors c-Myc, c-Jun, and RelA/NF-κB. These results extend our knowledge of the osteocytic response to fluid flow, most notably up-regulation of Cxcl1 and Cxcl2 as possible paracrine agents for osteoblastic and osteoclastic recruitment. Moreover, these results demonstrate the utility of integrative, high-throughput approaches in place of a traditional candidate approach for identifying novel mechano-sensitive signaling molecules.

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Regulation of gene expression and subcellular protein distribution in MLO-Y4 osteocytic cells by lysophosphatidic acid: Relevance to dendrite outgrowth

Cited by 13 publications

References 57 publications

Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass

Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass

Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering

Integrative transcriptomic and proteomic analysis of osteocytic cells exposed to fluid flow reveals novel mechano-sensitive signaling pathways

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