br The embryological and physiological

The embryological and physiological roles of ATX ATX is a vital enzyme that is needed for early embryological development. ATX knockout (KO) (ENPP2−/−) embryos die in utero on average at day 9.5 with vascular and neural tube defects [30], [73], [74], [75]. In these mice, malformations in the allantois, neural tube and headfold are detected by day 8.5, and by day 10.5 embryos become necrotic and are reabsorbed [76]. Normally, extra-embryonic endothelial ML324 sale remodel to create a vascular network that connects with the embryo from days 8.5 to 9.5, allowing the yolk sac to function as the main nutrient source. ENPP2−/− embryos have increased expression of VEGF mRNA, consistent with hypoxic conditions in the absence of a functional vascular system [30], [31]. This illustrates the importance of LPA in vascular development. Neural tube closure begins at day 8.5 and closure defects in ENPP2−/− embryos have been attributed to a local deficiency in ATX expression [30]. In ENPP2−/− embryo explants, these folding abnormalities are abrogated by exogenous addition of LPA [77]. The role of ATX in vascular and neural development has also been confirmed in zebrafish [76], [78]. ATX regulates oligodendrocyte differentiation in developing zebrafish hindbrain [79] and the correct left–right asymmetry for normal organ morphogenesis through Wnt-dependent pathways [80]. ENPP2+/− mice are viable, and express both half the levels of ATX and LPA compared to normal mice. However, they are hyper-responsive to hypoxia-induced vasoconstriction and remodeling and they develop pulmonary hypertension [81]. The importance of ATX to proper neuronal development and function is also reflected by high ATX mRNA in adult neuronal tissues [82] (Fig. 2). ATX mRNA levels are also high in adipose tissues (Fig. 2) and this will be discussed further in Section 4.3[83]. Physiologically, the most important role of ATX after birth is probably in wound healing and tissue remodeling. LPA is a potent activator of platelet aggregation and it stimulates the growth and migration of fibroblasts, vascular smooth muscle cells, endothelial cells and keratinocytes [36]. In fact, fibroblasts are second only to brain/spinal cord tissue as the highest expressers of ATX mRNA (Fig. 2). Increased ATX activity is found in blister fluid where local production of LPA promotes re-epithelialization [84]. ATX expression and LPA production are increased in rabbit aqueous humor following corneal freeze wounds [85]. Recently discovered roles for ATX include hair follicle morphogenesis [86], bone mineralization [87] and myeloid differentiation in human bone marrow [88]. ATX/LPA signaling also remodels luteal tissue in regressing corpora lutea of cycling rats by recruiting phagocytes and proliferating fibroblasts [89]. ATX expression is also upregulated in microglia in response to oxidative stress. This protects microglia cells against damage from H2O2, an effect which is partially reversed in the presence of the mixed LPA1/3 antagonist Ki16425 [90]. ATX is expressed in high endothelial venules (HEVs) in lymph nodes and other secondary lymphoid tissues [91] and mediates lymphocyte extravasation, which is crucial for maintaining immune homeostasis [92], [93]. However, in chronically inflamed tissues, ATX mediates lymphocyte trafficking and upregulates cytokine production in response to repeated microinjuries and incomplete tissue repair [94], [95], [96].
Acute physiological inflammation versus chronic pathological inflammation
The role of ATX in inflammatory diseases
Recent insights into ATX and cancer Ultimately, pathological ATX/LPA signaling is more complicated than simply upregulated ATX production, and this has been best studied in cancer. LPA signaling can be roughly divided into three distinct domains: ATX activity, LPA receptors, and extracellular LPA degradation by the ecto-activity of lipid phosphate phosphatases (LPPs) [7], [60], [146]. In many cancers, ATX protein is increased leading to higher LPA levels in the tumor. Cancer cells also have increased expression of LPA receptors on their cell surface compared to normal and benign cells, and downregulated expression of LPPs [7], [60]. Thus, a triad of increased LPA production by ATX, increased LPA receptor expression and decreased LPP activity to degrade LPA on the cell surface creates the perfect storm for cancer proliferation, migration, metastasis and therapy resistance, which we have previously reviewed [7], [44], [60], [146]. It is not known if other ATX-mediated inflammatory diseases follow the cancer model by increasing LPA receptor expression and decreasing LPP activity, in addition to increasing ATX production. However, the importance of studying LPA signaling in terms of the whole-picture of the ATX–LPA–LPP axis is becoming better appreciated [147], [148].