Abstract
Poorly controlled diabetes mellitus (DM) exacerbates periodontitis (PD) development and progression.
In addition, the management of PD in patients with uncontrolled DM remains a clinical challenge. In fact, PD
constitutes the sixth most frequent complication of DM. However, the mechanisms by which DM compounds
PD are not fully understood, although a heightened inflammatory response plays a central role. Among the major
inflammatory mediators of DM is CXCL10. Interestingly, CXCL10 also plays an important role in PD. CXCL10
expression levels are higher in periodontally diseased tissues and in the serum of patients with PD. Moreover,
our laboratory has shown that the CXCL10-CXCR3 axis is fundamental for PD development. We demonstrated
that experimentally-induced periodontal bone loss (EPD), in mice, is significantly reduced when the CXCL10
receptor CXCR3, is deleted. Moreover, systemic, and local delivery of a CXCR3 antagonist attenuates EPD,
pointing to the targeting of CXCL10 as a potential intervention for PD. Given that DM exacerbates PD, and the
key role of CXCL10 as an inflammatory mediator of DM and PD, we hypothesize that CXCL10 is central in
mediating the detrimental effects of DM and PD. Thus, targeting the CXCL10-CXCR3 axis should ameliorate the
deleterious effects of DM in the periodontium and is a potential therapeutic strategy for the periodontal
management of patients with uncontrolled DM. To accomplish our goal, we have two specific aims (SA). SA1:
Further elucidate the role of CXCL10 in the periodontium by deleting CXCL10 (SA1a) and by administering
CXCL10 systemically (SA1b). SA2: Determine the inhibition of periodontal destruction by a CXCR3 antagonist
in mice with DM. In this aim, we will evaluate if local delivery of nanoparticles containing a CXCR3 antagonist,
AMG-487, could mitigate the effects of DM in the PD. In brief, DM will be induced in mice, EPD will be developed,
and AMG-487 will be delivered locally in slow-releasing nanoparticles. These experiments will provide proof-of-
principle evidence for targeting CXCL10-CXCR3 signaling in periodontal inflammation in patients with DM. The
long-term goal of our research is to dissect the role of CXCL10 in the exacerbation of PD by DM and to lay the
foundation for developing a novel therapeutic approach to assist in the periodontal treatment of patients with
uncontrolled diabetes.
