https://sites.bu.edu/chenlab/files/2014/01/38_McBeathDevCell_04.pdf

Cell shape, cytoskeletal tension, and rhoa regulate stem cell lineage commitment

Osteoblast adhesion on biomaterials.

The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.

/pdf/the-extracellular-matrix-a-dynamic-niche-in-cancer-21xcbo41km.pdf

The extracellular matrix: A dynamic niche in cancer progression

Stem-cell populations are established in 'niches'--specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics.

/pdf/the-stem-cell-niche-as-an-entity-of-action-2c65sw34hb.pdf

The stem-cell niche as an entity of action

Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.

/pdf/cytokines-in-atherosclerosis-pathogenic-and-regulatory-k5l4m0ggqp.pdf

Cytokines in atherosclerosis: pathogenic and regulatory pathways.

Cell-mediated (type-1) immunity is necessary for immune protection against most intracellular pathogens and, when excessive, can mediate organ-specific autoimmune destruction. Mice deficient in Eta-1 (also called osteopontin) gene expression have severely impaired type-1 immunity to viral infection [herpes simplex virus–type 1 (KOS strain)] and bacterial infection ( Listeria monocytogenes ) and do not develop sarcoid-type granulomas. Interleukin-12 (IL-12) and interferon-γ production is diminished, and IL-10 production is increased. A phosphorylation-dependent interaction between the amino-terminal portion of Eta-1 and its integrin receptor stimulated IL-12 expression, whereas a phosphorylation-independent interaction with CD44 inhibited IL-10 expression. These findings identify Eta-1 as a key cytokine that sets the stage for efficient type-1 immune responses through differential regulation of macrophage IL-12 and IL-10 cytokine expression.

https://science.sciencemag.org/content/sci/287/5454/860.full.pdf

Eta-1 (Osteopontin): An Early Component of Type-1 (Cell-Mediated) Immunity

The CD44 family of surface receptors regulates adhesion, movement, and activation of normal and neoplastic cells. The cytokine osteopontin (Eta-1), which regulates similar cellular functions, was found to be a protein ligand of CD44. Osteopontin induces cellular chemotaxis but not homotypic aggregation, whereas the inverse is true for the interaction between CD44 and a carbohydrate ligand, hyaluronate. The different responses of cells after CD44 ligation by either osteopontin or hyaluronate may account for the independent effects of CD44 on cell migration and growth. This mechanism may also be exploited by tumor cells to promote metastasis formation.

https://science.sciencemag.org/content/sci/271/5248/509.full.pdf

Receptor-Ligand Interaction Between CD44 and Osteopontin (Eta-1)

Neutrophil-independent macrophage re- sponses are a prominent part of delayed-type im- mune and healing processes and depend on T cell- secreted cytokines. An important mediator in this setting is the phosphoprotein osteopontin, whose secretion by activated T cells confers resistance to infection by several intracellular pathogens through recruitment and activation of macrophages. Here, we analyze the structural basis of this activity fol- lowing cleavage of the phosphoprotein by thrombin into two fragments. An interaction between the C-terminal domain of osteopontin and the recep- tor CD44 induces macrophage chemotaxis, and engagement of 3-integrin receptors by a nonover- lapping N-terminal osteopontin domain induces cell spreading and subsequent activation. Serine phosphorylation of the osteopontin molecule on specific sites is required for functional interaction with integrin but not CD44 receptors. Thus, in addition to regulation of intracellular enzymes and substrates, phosphorylation also regulates the bio- logical activity of secreted cytokines. These data, taken as a whole, indicate that the activities of distinct osteopontin domains are required to coor- dinate macrophage migration and activation and may bear on incompletely understood mechanisms of delayed-type hypersensitivity, wound healing, and granulomatous disease. J. Leukoc. Biol. 72: 752-761; 2002.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.72.4.752

Phosphorylation-dependent interaction of osteopontin with its receptors regulates macrophage migration and activation

Ground bone or cartilage particles are demineralized by extraction with a low ionic strength buffer such as 20 mM HEPES containing a chelating agent and protease inhibitors, then extracted with an acidic solution such as 0.3 M citric acid, pH 4.0, containing protease inhibitors. The extracted material generally contains less than 2 % by weight phosphate and less than 100 mM calcium. The phosphate content can be further reduced by treatment of the matrix with acid phosphatase, which removes residual organic phosphate. The material is useful in a method of treatment of vesicoureteral reflux and other disorders where a bulking agent is effective in correcting the defect.

Injectable non-immunogenic cartilage and bone preparation

Mechanical perturbation has been shown to modulate a wide variety of changes in second message signals and patterns of gene expression in osteoblasts. Embryonic chick osteoblasts were subjected to a dynamic spatially uniform biaxial strain (1.3% applied strain) at 0.25 Hz for a single 2-h period, and osteopontin (OPN), an Arg-Gly-Asp (RGD)-containing protein, was shown to be a mechanoresponsive gene. Expression of opn mRNA reached a maximal 4-fold increase 9 h after the end of the mechanical perturbation that was not inhibited by cycloheximide, thus demonstrating that mechanoinduction of opn expression is a primary response through the activation of pre-existing transcriptional factors. The signal transduction pathways, which mediated the increased expression of opn in response to mechanical stimuli, were shown to be dependent on the activation of a tyrosine kinase(s) and protein kinase A (PKA) or a PKA-like kinase. Selective inhibition of protein kinase C (PKC) had no effect on the mechanoinduction of osteopontin even though opn has been demonstrated to be an early response gene to phorbol 12-myristate 13-acetate (PMA) stimulation. Mechanotransduction was dependent on microfilament integrity since cytochalasin-D blocked the up-regulation of the opn expression; however, microfilament disruption had no effect on the PMA induction of the gene. The microtubule component of the cytoskeleton was not related to the mechanism of signal transduction involved in controlling opn expression in response to mechanical stimulation since colchicine did not block opn expression. Mechanical stimulus was shown to activate focal adhesion kinase (FAK), which specifically became associated with the cytoskeleton after mechanical perturbation, and its association with the cytoskeleton was dependent on tyrosine kinase activity. In conclusion, these results demonstrate that the signal transduction pathway for mechanical activation of opn is uniquely dependent on the structural integrity of the microfilament component of the cytoskeleton. In contrast, the PKC pathway, which also activates this gene in osteoblasts, acts independently of the cytoskeleton in the transduction of its activity.

Signal transduction of mechanical stimuli is dependent on microfilament integrity : Identification of osteopontin as a mechanically induced gene in osteoblasts

Samy Ashkar

Papers

Eta-1 (Osteopontin): An Early Component of Type-1 (Cell-Mediated) Immunity

Receptor-Ligand Interaction Between CD44 and Osteopontin (Eta-1)

Phosphorylation-dependent interaction of osteopontin with its receptors regulates macrophage migration and activation

Injectable non-immunogenic cartilage and bone preparation

Signal transduction of mechanical stimuli is dependent on microfilament integrity : Identification of osteopontin as a mechanically induced gene in osteoblasts