Osteopontin Signals through Calcium and Nuclear Factor of Activated T Cells (NFAT) in Osteoclasts

Tanabe, Natsuko; Wheal, Benjamin D.; Kwon, Jin-Sook; Chen, Hong H.; Shugg, Ryan P.P.; Sims, Stephen M.; Goldberg, Harvey A.; Dixon, S. Jeffrey

doi:10.1074/jbc.m111.295048

Cited by 45 publications

(46 citation statements)

References 60 publications

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“…Cytosolic Ca 2+ is an important regulator of cell motility, and contributes to organization of the cytoskeleton, actin dynamics, directionality, and cell‐matrix interactions in a number of cell types . For example, integrin binding can lead to elevation of cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) through release from intracellular stores and influx . Elevation of [Ca 2+ ] i is thought to regulate cell adhesion and migration in rapidly migrating cells such as neutrophils and eosinophils .…”

Section: Introductionmentioning

confidence: 99%

“…Osteoclasts adhere to mineralized substrate predominantly through the binding of αvβ3 integrin to matrix proteins, and integrin blockers disrupt motility and resorption . Recent studies reveal that the fundamental process of osteoclast binding to matrix proteins such as osteopontin activates Ca 2+ signaling and downstream effectors such as nuclear factor of activated T cells (NFAT) . Adhesion to the substrate is a crucial element in osteoclast motility, with actin cytoskeletal dynamics required for cell migration .…”

Section: Introductionmentioning

confidence: 99%

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Subcellular Elevation of Cytosolic Free Calcium Is Required for Osteoclast Migration

Wheal

Beach

Tanabe

et al. 2013

Journal of Bone and Mineral Research

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Osteoclasts are multinucleated cells responsible for the resorption of bone and other mineralized tissues during development, physiological remodeling, and pathological bone loss. Osteoclasts have the ability to resorb substrate while concurrently migrating. However, the subcellular processes underlying migration are not well understood. It has been proposed that, in other cell types, cytosolic free Ca 2þ concentration ([Ca 2þ ] i ) regulates cell protrusion as well as retraction. Integration of these distinct events would require precise spatiotemporal patterning of subcellular Ca 2þ . The large size of osteoclasts offers a unique opportunity to monitor patterns of Ca 2þ during cell migration. We used ratiometric imaging to map [Ca 2þ ] i within rat and mouse osteoclasts. Migration was characterized by lamellipodial outgrowth at the leading edge, along with intermittent retraction of the uropod. Migrating osteoclasts displayed elevation of [Ca 2þ ] i in the uropod, that began prior to retraction. Dissipation of this [Ca 2þ ] i gradient by loading osteoclasts with the Ca 2þ chelator BAPTA abolished uropod retraction, on both glass and mineralized substrates. In contrast, elevation of [Ca 2þ ] i using ionomycin initiated prompt uropod retraction. To investigate downstream effectors, we treated cells with calpain inhibitor-1, which impaired uropod retraction. In contrast, lamellipodial outgrowth at the leading edge of osteoclasts was unaffected by any of these interventions, indicating that the signals regulating outgrowth are distinct from those triggering retraction. The large size of mature, multinucleated osteoclasts allowed us to discern a novel spatiotemporal pattern of Ca 2þ involved in cell migration. Whereas localized elevation of Ca 2þ is necessary for uropod retraction, lamellipod outgrowth is independent of Ca 2þ -a heretofore unrecognized degree of specificity underlying the regulation of osteoclast migration.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Subcellular Elevation of Cytosolic Free Calcium Is Required for Osteoclast Migration

Wheal

Beach

Tanabe

et al. 2013

Journal of Bone and Mineral Research

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“…Throughout the processes of osteoblast differentiation, matrix mineralization, tissue repair and bone regeneration, the expression and levels of OPN and VEGF vary (Table 1) [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

Section: Skeletal Healing and Remodelingmentioning

confidence: 99%

“…OPN mediates attachment of osteoclasts to bone mineral to initiate bone resorption and remodeling [15]. Also, OPN enhances osteoclast survival by a Ca 2+ -NFAT-dependent pathway [16] as pore size and pore geometry, determine their surface hydrophilicity and permeability, thus affecting diffusion, oxygen tension and nutrient exchange for bone marrow stem cells. Larger pore sizes with higher diethyl fumarate incorporation in poly-propylene fumarate scaffolds lead to a substantial increase in the expression of BMP-2, fibroblast growth factor 2, TGF-β1 (tumor growth factor-β1), VEGF, the transcription factor RUNX2 and osteocalcin over scaffolds with smaller pore sizes.…”

Section: ] Osteoblastsmentioning

confidence: 99%

Interactions between osteopontin and vascular endothelial growth factor: Implications for skeletal disorders

Ramchandani

Weber

2015

Bone

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“…This is not surprising, since these integrin-mediated pathways have been shown to involve the phosphorylation cascades associated with FAK or Src kinases (Wu et al, 2001). Integrin-mediated ion channel effects can be found in additional cell types, ranging from osteoclasts, where activation of β 1 and β 3 integrins upregulated cytosolic Ca 2+ (Chenu et al, 1994; Tanabe et al, 2011), to monocytes, where K + currents are modulated by VLA-4 (α 4 β 1 ) integrins (Colden-Stanfield, 2002; Colden-Stanfield and Scanlon, 2000). Thus, a wide variety of integrin-mediated ion channel effects have been described in multiple cell types, suggesting that they may also play a role in cardiomyocyte electrical homeostasis.…”

Section: Integrin Signaling In Ionic Homeostasis In Nonmyocytesmentioning

confidence: 99%

A potential role for integrin signaling in mechanoelectrical feedback

Dabiri

Lee

Parker

2012

Progress in Biophysics and Molecular Biology

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Certain forms of heart disease involve gross morphological changes to the myocardium that alter its hemodynamic loading conditions. These changes can ultimately lead to the increased deposition of extracellular matrix (ECM) proteins, such as collagen and fibronectin, which together work to pathologically alter the myocardium’s bulk tissue mechanics. In addition to changing the mechanical properties of the heart, this maladaptive remodeling gives rise to changes in myocardium electrical conductivity and synchrony since the tissue’s mechanical properties are intimately tied to its electrical characteristics. This phenomenon, called mechanoelectrical coupling (MEC), can render individuals affected by heart disease arrhythmogenic and susceptible to sudden cardiac death (SCD). The underlying mechanisms of MEC have been attributed to various processes, including the action of stretch activated channels and changes in troponin C-Ca2+ binding affinity. However, changes in the heart post infarction or due to congenital myopathies are also accompanied by shifts in the expression of various molecular components of cardiomyocytes, including the mechanosensitive family of integrin proteins. As transmembrane proteins, integrins mechanically couple the ECM with the intracellular cytoskeleton and have been implicated in mediating ion homeostasis in various cell types, including neurons and smooth muscle. Given evidence of altered integrin expression in the setting of heart disease coupled with the associated increased risk for arrhythmia, we argue in this review that integrin signaling contributes to MEC. In light of the significant mortality associated with arrhythmia and SCD, close examination of all culpable mechanisms, including integrin-mediated MEC, is necessary.

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Osteopontin Signals through Calcium and Nuclear Factor of Activated T Cells (NFAT) in Osteoclasts

Cited by 45 publications

References 60 publications

Subcellular Elevation of Cytosolic Free Calcium Is Required for Osteoclast Migration

Subcellular Elevation of Cytosolic Free Calcium Is Required for Osteoclast Migration

Interactions between osteopontin and vascular endothelial growth factor: Implications for skeletal disorders

A potential role for integrin signaling in mechanoelectrical feedback

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