Lysophosphatidic acid (LPA) 18:1 transcriptional regulation of primary human gingival fibroblasts

Abstract

The pleiotropic, bioactive lipid lysophosphatidic acid [(LPA), 1-acyl-sn-glycerol-3-phosphate] exerts critical regulatory actions in physiology and pathophysiology in many systems. It is present in normal bodily fluids, and is elevated in pathology (1). In vivo, “LPA” exists as distinct molecular species, each having a single fatty acid of varying chain length and degree of unsaturation covalently attached to the glycerol backbone via an acyl, alkyl, or alkenyl link. These species differ in affinities for the individual LPA receptors [(LPARs), LPA1-6] and coupling to G proteins (2). However, LPA 18:1 has been and continues to be the most commonly utilized species in reported studies. The actions of “LPA” remain poorly defined in oral biology and pathophysiology. Our laboratory has addressed this knowledge gap by studying in vitro the actions of the major human salivary LPA species [18:1, 18:0, and 16:0 (3)] in human oral cells [4], [5], [6], [7]. This includes gingival fibroblasts (GF), which our flow cytometry data from multiple donors found that they express LPA1-5 (6). We have also reported that these species are ten-fold elevated to pharmacologic levels in the saliva and gingival crevicular fluid obtained from patients with moderate–severe periodontitis (8). As the potential of LPA to regulate transcriptional activity had not been examined in the oral system, this study used whole human genome microarray analysis to test the hypothesis that LPA 18:1-treated human GF would show significant changes in gene transcripts relevant to their biology, wound-healing, and inflammatory responses. LPA 18:1 was found to significantly regulate a large, complex set of genes critical to GF biology in these categories and to periodontal disease. The raw data has been deposited at NCBI's GEO database as record GSE57496.

Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation

“…In both zebrafish and mice, ATX-LPA 1 signaling contributes to proliferation of chondrocytes by promoting S-phase entry and regulating fibronectin assembly, leading to proper cartilage formation [ 73 ]. Finally, C18:1-LPA signaling may be a master transcriptional regulator of primary human gingival fibroblasts that mediate gingival repair, but under chronic inflammatory conditions it promotes periodontal disease [ 74 , 75 , 76 ].…”

Entering, Linked with the Sphinx: Lysophosphatidic Acids Everywhere, All at Once, in the Oral System and Cancer

“…Given the extent of LPA’s regulatory actions on oral fibroblasts, we hypothesized that LPA would control multiple transcripts related to wound healing and inflammation and designed a microarray experiment based on stimulation of primary GF (n = 3; three pools of three healthy young donors each) stimulated with the most widely used LPA species, 18:1, and explored the results by Ingenuity Pathway Analysis (IPA) of molecular interaction pathways. LPA exerted profound transcriptional control over >60 key GF inflammation-related cytokines, their receptors, enzymes, and other mediators [ 41 , 42 ]. Other investigators [ 43 , 44 ] have reported that LPA and its receptors control the biology of human dental pulp fibroblasts and of human oral keratinocytes, respectively.…”

“…We showed that human GF make ATX (ENPP2) transcripts and that they also produce several LPA species in a time-dependent manner [ 42 ], as do human PDLF. Of great interest for PDD, which has a genetic susceptibility component, we saw a marked induction of ATX/ENPP2 in the third donor group of our microarray survey at both 2 h and 8 h vs. the small but significant changes in the first and second groups at 2 h and the decreases (not significant) at 8 h for these two groups [ 41 , 42 ]. The enhanced response in the third group was likely due to a donor with a genetically over-responsive immune system, which would predispose them to develop PDD at a later age.…”