JAK Inhibition Prevents Bone Loss and Reduces Inflammation in Experimental Periodontitis.

Abstract

Aims: This study aimed to investigate the role of Janus kinase (JAK) signaling in the pathogenesis of periodontitis by evaluating the effects of pharmacological inhibition of JAK isoforms (JAK1 and JAK3) on periodontal inflammation and ligature-induced alveolar bone loss.

Methods: Experimental periodontitis (EP) was induced by ligature placement around the mandibular first molars of rats. Concurrently, animals (n = 10 per group) received either a JAK1-3 inhibitor (JAK1-3i group), a JAK3 inhibitor (JAK3i group), or distilled water (EP group) via daily intragastric gavage for 7 days. A control group received only distilled water without ligature placement. Following euthanasia, the mandibles were evaluated using microcomputed tomography for bone loss, stereometric analysis for inflammatory infiltrate and blood vessels, Second Harmonic Generation Microscopy for collagen quantification, and immunohistochemistry to quantify CD45+ and CD3+ cell populations. Gingival tissues were assessed for inflammatory markers by RT-qPCR (Il-6, Tnf-α, and Rankl) and ELISA (TNF-α).

Results: Ligature placement resulted in significant alveolar bone loss, increased osteoclast numbers, leukocyte infiltration, extracellular matrix degradation, and elevated expression of inflammatory markers. Treatment with both JAK1-3i and JAK3i effectively prevented bone loss and reduced osteoclast numbers. Histological and stereometric analyses showed reduced inflammatory infiltrate and improved tissue organization in both treated groups. JAK1-3i preserved collagen content more effectively and significantly reduced the number of CD45+ cells. Compared to the Experimental Periodontitis (EP) group, both inhibitors significantly downregulated the mRNA expression of Il-6, Tnf-α, and Rankl, and also reduced TNF-α protein levels in gingival tissues.

Conclusion: Collectively, the findings establish a mechanistic link between JAK signaling and inflammation-driven periodontal tissue destruction, providing new insights into the cellular and molecular events underlying the pathogenesis of experimental periodontitis.