Beyond vitamin D: integrating nuclear receptor signaling networks in periodontal health and disease.

Vitamin D receptor (VDR) signaling has been studied extensively in periodontology, yet the broader nuclear receptor superfamily remains underexplored. We examined the roles of four nuclear receptor family members: VDR, peroxisome proliferator-activated receptor gamma (PPAR-γ), retinoid X receptor alpha (RXR-α), and farnesoid X receptor (FXR) in periodontal health and disease across the continuum from gingival health through gingivitis to periodontitis. However, most functional and mechanistic evidence is derived from established or experimental periodontitis, whereas evidence from periodontal health and gingivitis remains limited. VDR, PPAR-γ, and FXR have been associated with periodontal immune and bone responses through distinct but intersecting pathways. VDR induces cathelicidin and modulates RANKL/OPG expression. PPAR-γ suppresses NF-κB-mediated cytokine production and promotes M2 macrophage polarization. FXR agonists reduce osteoclastogenesis while enhancing osteoblast differentiation in rodent periodontitis models. In general nuclear receptor biology, RXR-α is a heterodimerization partner for VDR, PPAR-γ, and FXR and may represent a putative integrative node in periodontal signaling. However, the direction and magnitude of RXR-α expression changes remain inconsistent, and the effects of RXR ligand activation on VDR and PPAR-γ transcriptional activity in periodontal tissues remain to be established. Major gaps remain: human data on PPAR-γ and FXR are scarce, localized nuclear receptor activation has not advanced to clinical trials, and nuclear receptor interactions with periodontal biofilms remain uncharacterized. A network-centered framework prioritizing RXR-mediated heterodimerization, localized ligand delivery, nuclear receptor-selective modulators, and genotype-guided supplementation may help define future research directions, but these applications require further validation.