ABSTRACT
Lysophosphatidic acid (LPA) signaling has the potential to be of therapeutic value in periodontal disease (PD).
LPA is central to homeostasis and pathophysiology, existing in bodily fluids at low levels in health, and
becoming elevated in inflammation and pathology. Key to periodontal disease (PD), LPA is essential to all
aspects of bone biology and inflammation (Jesionowska et al., 2014). The secreted enzyme autotaxin (ATX)
makes the majority of LPA and is found elevated in inflammatory pathophysiologies in other systems. In PD,
over-activation of inflammatory pathways leads to immune-mediated periodontal tissue and bone damage and
destruction. Therefore, LPA and ATX are likely to contribute significantly to the pathogenesis of PD. Our
central hypothesis is that LPA controls the expression of key inflammatory mediators that contribute to the
periodontal tissue destruction and bone loss. However, it is not known how LPA contributes to the hallmark of
PD, inflammation. Therefore, this proposal addresses the urgent need to correct this knowledge gap in order to
be able to pharmacologically modulate this central inflammatory mediator’s signaling system in PD. Our in
vitro studies with primary human gingival (GF) and periodontal ligament (PDLF) fibroblasts confirmed that they
express the LPA receptor (LPAR) subtypes LPA1-5 at high levels (Cerutis et al. 2010) and that LPA positively
regulates their in vitro wound-healing and regenerative responses (George et al., 2009) by signaling mainly
through LPA1 and LPA3. We also found elevated LPA levels (µM) in PD patient saliva and gingival crevicular
fluid (GCF) (Bathena et al. 2011), and that LPA profoundly regulates transcription of > 60 key inflammation-
related GF cytokines, their receptors, enzymes, and other mediators (Cerutis et al. 2015a) further supporting
our central hypothesis. Therefore, the rationale for this proposed research is that individual LPA subtypes may
be innovatively manipulated pharmacologically to treat PD by favoring oral healing. We will test our central
hypothesis using a mouse model of P. gingivalis- induced PD to answer several fundamental questions via
three specific aims: Aim 1. Determine if an LPA1 antagonist can prevent or reduce PD-induced periodontal
tissue and alveolar bone loss. Aim 2. Determine if an ATX inhibitor can prevent or reduce PD-induced
periodontal tissue and alveolar bone loss. Aim 3. Identify in vitro if the production of key PD inflammatory
molecules can be diminished via administration of LPA1 and/or LPA3 antagonists. We expect these studies to
provide a strong seminal foundation for defining the role of LPA in PD, and to identify the edg family LPAR
subtype(s) most associated with PD development and periodontal tissue and bone destruction. These studies
will advance the field of Periodontology by identifying the basic actions of LPA, a lipid mediator heretofore
unrecognized to contribute to PD pathogenesis. Expected results: the contribution of LPA and its receptors
interacting with known PD-regulatory cytokine networks will be able to be targeted and manipulated in new
ways to treat PD, which worsens many common health conditions like cardiovascular disease and diabetes.