Inhibiting fibroblast activation protein mitigates aging-related periodontitis by blocking nuclear factor kappa B-mediated osteoclastogenesis

  • Int Immunopharmacol. 2026 Jun 15:179:116647. doi: 10.1016/j.intimp.2026.116647.
Yuezhang Sun  1 ,  Haonan Zou  1 ,  Aimin Cui  1 ,  Hao Dong  1 ,  Abulizi Pawuziya  1 ,  Pengfei Zhao  2 ,  Jian Wang  3 ,  Wai Keung Leung  4 ,  Qi Wang  5
Affiliations
  • 1. State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • 2. Periodontology and Implant Dentistry Division, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
  • 3. State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China. Electronic address: [email protected].
  • 4. Periodontology and Implant Dentistry Division, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Sichuan Provincial Engineering Research Center of Oral Biomaterials, Sichuan University, Chengdu, China. Electronic address: [email protected].
PMID: 41966776 DOI: 10.1016/j.intimp.2026.116647
Abstract

Aging is closely associated with the progression of periodontitis, yet the mechanisms link between fibroblast dysfunction and periodontal tissue destruction remains unclear. This study investigates the role of fibroblast activation protein (FAP) in aging-related periodontitis and explores its therapeutic potential. In aging mice, we observed significant fibroblast dysfunction in periodontal tissues, characterized by FAP upregulation (p < 0.0001). Elevated FAP expression exacerbated periodontal destruction by enhancing collagenase activity and promoting osteoclast differentiation (p < 0.0001). Mechanistically, FAP activation in senescent gingival fibroblasts triggered the nuclear factor kappa B (NF-κB) signaling pathway (p < 0.01), driving inflammatory bone resorption. Pharmacological inhibition of FAP, both in vitro and in vivo, effectively attenuated periodontal inflammation, suppressed osteoclast activity (p < 0.0001), and preserved alveolar bone integrity in aging mice (p < 0.0001). These findings highlight FAP as a critical mediator of aging-related periodontal deterioration and propose FAP-targeted therapy as a novel strategy for mitigating periodontitis in the elderly. This study provides new insights into the interplay between fibroblast senescence, immune regulation, and tissue remodeling in age-related oral inflammatory diseases, offering a promising avenue for therapeutic intervention.

Keywords
Aging; Fibroblast; Fibroblast activation protein; Nuclear factor kappa B; Osteoclast; Periodontitis.
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