Several cytokines with major biological functions in inflammatory diseases exert their functions through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction pathway. JAKs phosphorylate the cytoplasmic domain of the receptor, inducing the activation of its substrates, mainly the proteins known as STATs. STATs bind to these phosphorylated tyrosine residues and translocate from the cytoplasm to the nucleus, further regulating the transcription of several genes that regulate the inflammatory response. The JAK/STAT signaling pathway plays a critical role in the pathogenesis of inflammatory diseases. There is also increasing evidence indicating that the persistent activation of the JAK/STAT signaling pathway is related to several inflammatory bone (osteolytic) diseases. However, the specific mechanism remains to be clarified. JAK/STAT signaling pathway inhibitors have gained major scientific interest to explore their potential in the prevention of the destruction of mineralized tissues in osteolytic diseases. Here, our review highlights the importance of the JAK/STAT signaling pathway in inflammation-induced bone resorption and presents the results of clinical studies and experimental models of JAK inhibitors in osteolytic diseases.

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.

Chalcones are phenolic compounds with biological properties. This study had the aim to evaluate the effects of topical administration of a new synthetic chalcone, Chalcone T4, in an animal model of periodontitis induced by ligature. Forty rats were distributed in the following experimental groups: negative control (without periodontitis and topical application of distilled water), positive control (periodontitis and topical application of distilled water), chalcone I and II (periodontitis and topical application of 0.6 mg/mL and 1.8 mg/mL, respectively). Chalcone or distilled water was administered into the gingival sulcus of the first molars daily for 10 days, starting with the ligature installation. The following outcomes were evaluated: alveolar bone loss (µCT and methylene blue dye staining), quantification of osteoclasts (histomorphometry), cell infiltrate and collagen content (stereometry), gene expression of mediators (Nfact11, Tnf-α, Mmp-13, iNos, Sod and Nrf2) by (RT-qPCR); expression of BCL-2 and Caspase-1 (immunohistochemistry). Chalcone T4 inhibited bone resorption and prevented collagen matrix degradation. Reduction in the expression of inflammatory markers (Nfact11, Tnf-α, Mmp-13, and Caspase-1), attenuation of oxidative stress (iNOS reduction, and increase in Sod), and pro-apoptotic effect of the compound (BCL-2 reduction), were associated its effects on periodontal tissues. Topical application of Chalcone T4 prevented bone resorption and inflammation, demonstrating potential in the adjunctive treatment of periodontitis.

Aim: To investigate whether pharmacological modulation of Nrf2 signaling influences oxidative stress, inflammatory responses, and periodontal tissue destruction in experimental ligature‐induced periodontitis. Methods: Ligature‐induced experimental periodontitis was established in rats treated with dimethyl fumarate (DMF), an Nrf2 activator, and/or ML385, a selective Nrf2 inhibitor. Alveolar bone loss, oxidative stress markers, inflammatory mediators, and histopathological changes were evaluated. Results: Nrf2 activation attenuated alveolar bone loss, reduced oxidative stress, and decreased inflammatory mediators, accompanied by improved periodontal tissue organization. In contrast, Nrf2 inhibition exacerbated inflammation and increased periodontal tissue destruction. Conclusion: Nrf2 signaling plays a regulatory role in periodontal inflammation and tissue breakdown. Pharmacological activation of Nrf2 exerts protective effects, whereas its inhibition aggravates disease severity.