Autotaxin/Lysophosphatidic Acid Axis Promotes Periodontitis by Modulating Macrophage Osteoclastogenesis and Inflammation

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AIM: To investigate the mechanism of the autotaxin/lysophosphatidic acid (ATX/LPA) axis in regulating osteoclastogenesis and inflammation in periodontitis. MATERIALS AND METHODS: The expression levels and clinical relevance of the ATX/LPA axis were studied by collecting clinical samples including gingiva and gingival crevicular fluid from periodontitis patients and healthy subjects. Subsequently, macrophage Atx knockout (CKO) mice and bone marrow-derived macrophages (BMDMs) were generated to investigate the role of the ATX/LPA axis in modulating osteoclastogenesis and inflammation during periodontitis development. Finally, the ATX inhibitor PF8380 was used to explore a promising therapeutic strategy for controlling periodontitis. Histomorphological, molecular and cytological analyses were performed using RNA sequencing, real-time polymerase chain reaction, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, micro-computed tomography, haematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, actin filament staining, pit resorption assay and flow cytometry. RESULTS: The expression of the ATX/LPA axis was more enhanced in the periodontitis group than that in the health group and was positively correlated with the severity of periodontitis. Subsequently, CKO mice showed milder inflammation and less bone resorption than wild-type (WT) mice of periodontitis. Following Porphyromonas gingivalis LPS stimulation, CKO-BMDMs were markedly suppressed in osteoclastogenesis and inflammation compared to WT-BMDMs. In addition, the mechanism of the ATX/LPA axis in regulating osteoclastogenesis may act synergistically with activated inflammation-related pathways by RNA sequencing. Finally, we used the ATX inhibitor PF8380 and found that PF8380 alleviated alveolar bone resorption in periodontitis mice and modulated BMDMs' osteoclast differentiation and phenotypic transformation. CONCLUSION: The ATX/LPA axis plays a significant regulatory role in osteoclastogenesis and osteoclast activity and may enable selective control of bone loss and inflammation in periodontitis. Therefore, targeting ATX inhibition may represent a novel therapeutic strategy for preventing alveolar bone resorption and periodontal inflammation in patients with periodontitis.

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