Porphyromonas gingivalis RagA Protein Induces RANKL-Independent Osteoclastogenesis
Abstract
Periodontal diseases (PD; gum diseases) are arguably the highest prevalent disease of mankind (Guinness World Records 2001). Emerging paradigms support that PD can predispose individuals to several systemic diseases, such as, cardiovascular disease, Rheumatoid arthritis, and Alzheimer's disease. Over-reaction of host immune responses to oral pathobionts, including, Porphyromonas gingivalis (Pg), is responsible for the development of pathogenic inflammatory bone resorption lesions of PD. Pg present in deep, but not shallow, periodontal pockets possess Rag gene locus distinctively. However, possible pathogenic roles of RagA and RagB proteins encoded in Rag locus of Pg are largely unknown. This study aims to investigate the possible pathogenic effects of RagA/B on inflammatory bone destructive responses by monocytes. Recombinant RagA/B proteins were applied to mouse RAW264.7 monocyte-like cells to monitor 1) proinflammatory cytokine productions, 2) cell-proliferation, and 3) osteoclast (OC)-genesis. The effect of RagA on bone resorption was investigated using a ligature-induced PD mouse model. RagA significantly promoted cell-proliferation and productions of TNF-α and IL-6. Despite the absence of RANKL, RagA, but not RagB, induced TRAP-positive multinucleated cells accompanied by elevated pit area, as well as upregulated mRNA expressions of ocstamp, dcstamp, and nfatc1. Both RagA and RagB promoted the phosphorylation of three key MAPKs, including ERK, JNK, and p38. RagA promoted significantly more alveolar bone resorption in the mice compared with RagB or control ligature alone. These results indicated that RagA, not only elicits proinflammatory responses, but also induces OC-genesis in a RANKL-independent manner, potentially contributing to the pathogenesis of PD.
SUPPORT FUNDING/GRANT NUMBER: NIH grants DE027851, DE028715, DE029709, DE331851, and T34 GM145509. Maria Castellon was supported by U-RISE@NSU grant (GM145509)
Faculty Sponsors
Dr. Toshihisa Kawai
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-3-2024 12:30 PM
End Date
4-4-2024 1:30 PM
Porphyromonas gingivalis RagA Protein Induces RANKL-Independent Osteoclastogenesis
Alvin Sherman Library
Periodontal diseases (PD; gum diseases) are arguably the highest prevalent disease of mankind (Guinness World Records 2001). Emerging paradigms support that PD can predispose individuals to several systemic diseases, such as, cardiovascular disease, Rheumatoid arthritis, and Alzheimer's disease. Over-reaction of host immune responses to oral pathobionts, including, Porphyromonas gingivalis (Pg), is responsible for the development of pathogenic inflammatory bone resorption lesions of PD. Pg present in deep, but not shallow, periodontal pockets possess Rag gene locus distinctively. However, possible pathogenic roles of RagA and RagB proteins encoded in Rag locus of Pg are largely unknown. This study aims to investigate the possible pathogenic effects of RagA/B on inflammatory bone destructive responses by monocytes. Recombinant RagA/B proteins were applied to mouse RAW264.7 monocyte-like cells to monitor 1) proinflammatory cytokine productions, 2) cell-proliferation, and 3) osteoclast (OC)-genesis. The effect of RagA on bone resorption was investigated using a ligature-induced PD mouse model. RagA significantly promoted cell-proliferation and productions of TNF-α and IL-6. Despite the absence of RANKL, RagA, but not RagB, induced TRAP-positive multinucleated cells accompanied by elevated pit area, as well as upregulated mRNA expressions of ocstamp, dcstamp, and nfatc1. Both RagA and RagB promoted the phosphorylation of three key MAPKs, including ERK, JNK, and p38. RagA promoted significantly more alveolar bone resorption in the mice compared with RagB or control ligature alone. These results indicated that RagA, not only elicits proinflammatory responses, but also induces OC-genesis in a RANKL-independent manner, potentially contributing to the pathogenesis of PD.
SUPPORT FUNDING/GRANT NUMBER: NIH grants DE027851, DE028715, DE029709, DE331851, and T34 GM145509. Maria Castellon was supported by U-RISE@NSU grant (GM145509)
