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Activation of the Acquired Immune Response Reduces Coupled Bone Formation in Response to a Periodontal Pathogen¹

Yugal Behl^*, Michelle Siqueira^*, Javier Ortiz^*, Jingchao Li^*, Tesfahun Desta^*, Dan Faibish^* and Dana T. Graves^2,

^* Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118; and Department of Periodontics, University of Medicine and Dentistry, Newark, NJ 07101

Osteoimmunolgy involves the interaction of the immune system with skeletal elements. This interaction can lead to the formation of osseous lesions. To investigate how the acquired immune response could contribute to osteolytic lesions, we injected the periodontal pathogen Porphyromonas gingivalis adjacent to calvarial bone with or without prior immunization against the bacterium. Activation of the acquired immune response increased osteoclastogenesis and decreased coupled bone formation. The latter was accompanied by an increase in nuclear translocation of the transcription factor FOXO1 in vivo, increased apoptosis of bone-lining cells measured by the TUNEL assay and number of activated caspase-3 positive cells and a decrease in bone lining cell density. Further studies were conducted with MC3T3 osteoblastic cells. Apoptosis and increased FOXO1 DNA binding activity were induced when a combination of cytokines was tested, IL-β, TNF-, and IFN-. Knockdown of FOXO1 by small interfering RNA significantly reduced cytokine stimulated apoptosis, cleaved caspase-3/7 activity and decreased mRNA levels of the proapoptotic genes, TNF-, FADD, and caspase-3, -8, and -9. These results indicate that activation of the acquired immunity by a periodontal pathogen reduces the coupling of bone formation and resorption. This may occur by enhancing bone lining cell apoptosis through a mechanism that involves increased FOXO1 activation. These studies give insight into inflammatory bone diseases such as periodontal disease and arthritis were the formation of lytic lesions occurs in conjunction with deficient bone formation and activation of an acquired immune response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by Grants DE018307 and DE017332 from National Institutes of Dental and Craniofacial Research.

² Address correspondence and reprint requests to Dr. Dana T. Graves, Department of Periodontics, University of Medicine and Dentistry, Newark, NJ 07101. E-mail address: gravesdt{at}umdnj.edu

³ Abbreviations used in this paper: PTH, parathyroid hormone; siRNA, small interfering RNA; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP (TdT)-biotin nick end labeling.

⁴ The online version of this article contains supplementary material.