Loss of PTH 1 receptor signaling in periodontal cells drives cementum dysfunction and molar ankylosis in mice.

Abstract

Parathyroid hormone 1 receptor (PTH1R) signaling is critical for mineral ion homeostasis and skeletal development. Although its role in tooth root formation and eruption is established, its specific functions in adult periodontal tissues and craniofacial integrity remain incompletely defined. Here, we investigated the craniofacial and dentoalveolar phenotypes of mice with conditional deletion of PTH1R in DMP1-Cre-expressing cells. DMP1-Cre;PTH1Rfl/fl mutant mice exhibited craniofacial alterations, including reduced maxillary length and defects in the alveolar bone surrounding the molars, as revealed by micro-computed tomography and histological analysis. The mutant mice also displayed severe periodontal ligament (PDL) loss and extensive molar ankylosis, characterized by the direct fusion of alveolar bone to tooth roots, predominantly in regions of acellular cementum. In contrast, incisor development remained unaffected. PTH1R deficiency also resulted in pathological cementum overgrowth, disrupted PDL fiber organization, and decreased expression of key PDL matrix proteins, as evidenced by immunohistochemical and molecular analyses. Mechanistically, the loss of PTH1R enhanced Smad3 phosphorylation and upregulated Osterix, thereby promoting aberrant cementoblast differentiation and mineralization. Concurrently, Dkk1 expression was increased, leading to suppressed Wnt signaling. This evidence establishes PTH1R signaling in cementocytes as a central safeguard of cementum homeostasis and PDL integrity and demonstrates that its disruption induces pathological root-bone fusion and craniofacial abnormalities. These findings advance our understanding of the molecular mechanisms underlying adult periodontal tissue maintenance and open new opportunities for developing therapeutic strategies against ankylosis and related disorders by targeting PTH1R signaling.