{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T15:48:47Z","timestamp":1760888927069,"version":"3.40.3"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2008,12,1]],"date-time":"2008-12-01T00:00:00Z","timestamp":1228089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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-\u03b2, TNF-\u03b1, and IFN-\u03b3. 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-\u03b1, 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.<\/jats:p>","DOI":"10.4049\/jimmunol.181.12.8711","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:24:21Z","timestamp":1397863461000},"page":"8711-8718","source":"Crossref","is-referenced-by-count":51,"title":["Activation of the Acquired Immune Response Reduces Coupled Bone Formation in Response to a Periodontal Pathogen"],"prefix":"10.1093","volume":"181","author":[{"given":"Yugal","family":"Behl","sequence":"first","affiliation":[{"name":"Department of Periodontology and Oral Biology, Boston University School of Dental Medicine , Boston, MA 02118"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Siqueira","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Oral Biology, Boston University School of Dental Medicine , Boston, MA 02118"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Oral Biology, Boston University School of Dental Medicine , Boston, MA 02118"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingchao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Oral Biology, Boston University School of Dental Medicine , Boston, MA 02118"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tesfahun","family":"Desta","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Oral Biology, Boston University School of Dental Medicine , Boston, MA 02118"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Faibish","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Oral Biology, Boston University School of Dental Medicine , Boston, MA 02118"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana T","family":"Graves","sequence":"additional","affiliation":[{"name":"Department of Periodontics, University of Medicine and Dentistry , Newark, NJ 07101"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2008,12,15]]},"reference":[{"key":"2025032719421400800_R1","first-page":"181","article-title":"Osteoimmunology in skeletal cell biology and disease","volume-title":"Autoimmunity","year":"2008"},{"key":"2025032719421400800_R2","first-page":"31","article-title":"Osteoimmunology","volume-title":"Int. Arch. Allergy Immunol.","year":"2007"},{"key":"2025032719421400800_R3","first-page":"403","article-title":"Osteoimmunology: interactions of the bone and immune system","volume-title":"Endocr. Rev.","year":"2008"},{"key":"2025032719421400800_R4","first-page":"1","article-title":"The coupling of bone formation to bone resorption: a critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis","volume-title":"Metab. Bone Dis. Relat. Res.","year":"1982"},{"key":"2025032719421400800_R5","first-page":"79","article-title":"Osteoporosis, genetics and hormones","volume-title":"J. Mol. Endocrinol.","year":"2001"},{"key":"2025032719421400800_R6","first-page":"1151","article-title":"Commentary on clinical safety of recombinant human parathyroid hormone 1\u201334 in the treatment of osteoporosis in men and postmenopausal women","volume-title":"J. Bone Miner. Res.","year":"2002"},{"key":"2025032719421400800_R7","first-page":"613","article-title":"Pathophysiology of myeloma bone disease","volume-title":"Best Pract. Res. Clin. Haematol.","year":"2007"},{"key":"2025032719421400800_R8","first-page":"447","article-title":"Diabetes causes decreased osteoclastogenesis, reduced bone formation, and enhanced apoptosis of osteoblastic cells in bacteria stimulated bone loss","volume-title":"Endocrinology","year":"2004"},{"key":"2025032719421400800_R9","first-page":"6274s","article-title":"Wnt antagonism in multiple myeloma: a potential cause of uncoupled bone remodeling","volume-title":"Clin. Cancer Res.","year":"2006"},{"key":"2025032719421400800_R10","first-page":"775","article-title":"Dendritic cells at the osteo-immune interface: implications for inflammation-induced bone loss","volume-title":"J. Bone Miner. Res.","year":"2007"},{"key":"2025032719421400800_R11","first-page":"361","article-title":"Fundamental mechanisms of host immune responses to infection","volume-title":"J. Periodontal Res.","year":"2006"},{"key":"2025032719421400800_R12","first-page":"586","article-title":"Interleukin 18 and periodontal disease","volume-title":"J. Dent. Res.","year":"2007"},{"key":"2025032719421400800_R13","first-page":"975","article-title":"Osteoblast apoptosis and bone turnover","volume-title":"J. Bone Miner. Res.","year":"2001"},{"key":"2025032719421400800_R14","first-page":"15","article-title":"Diabetes-enhanced inflammation and apoptosis: impact on periodontal pathology","volume-title":"J. Dent. Res.","year":"2006"},{"key":"2025032719421400800_R15","first-page":"709","article-title":"Regulation of apoptosis in osteoclasts and osteoblastic cells","volume-title":"Biochem. Biophys. Res. Commun.","year":"2005"},{"key":"2025032719421400800_R16","first-page":"1492","article-title":"Quantifying osteoblast and osteocyte apoptosis: challenges and rewards","volume-title":"J. Bone Miner. Res.","year":"2007"},{"key":"2025032719421400800_R17","first-page":"115","article-title":"Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis","volume-title":"Endocr. Rev.","year":"2000"},{"key":"2025032719421400800_R18","first-page":"3554","article-title":"Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice","volume-title":"Endocrinology","year":"2004"},{"key":"2025032719421400800_R19","first-page":"50259","article-title":"Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism","volume-title":"J. Biol. Chem.","year":"2003"},{"key":"2025032719421400800_R20","first-page":"143","article-title":"Mineralized bone nodules formed in vitro from enzymatically released rat calvaria cell populations","volume-title":"Calcif. Tissue Int.","year":"1986"},{"key":"2025032719421400800_R21","first-page":"181","article-title":"Bone and cartilage formation in diffusion chambers by subcultured cells derived from the periosteum","volume-title":"Bone","year":"1990"},{"key":"2025032719421400800_R22","first-page":"475","article-title":"Impaired osteoblastogenesis in myeloma bone disease: role of upregulated apoptosis by cytokines and malignanat plasma cells","volume-title":"Br. J. Haematol.","year":"2004"},{"key":"2025032719421400800_R23","first-page":"421","article-title":"FoxOs at the crossroads of cellular metabolism, differentiation, and transformation","volume-title":"Cell","year":"2004"},{"key":"2025032719421400800_R24","first-page":"352","article-title":"Cell cycle and death control: long live Forkheads","volume-title":"Trends Biochem. Sci.","year":"2002"},{"key":"2025032719421400800_R25","first-page":"297","article-title":"The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation","volume-title":"Biochem. J.","year":"2004"},{"key":"2025032719421400800_R26","first-page":"689","article-title":"Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB\/Akt is off duty","volume-title":"J. Leukocyte Biol.","year":"2003"},{"key":"2025032719421400800_R27","first-page":"752","article-title":"FOXO transcription factors in cell-cycle regulation and the response to oxidative stress","volume-title":"Antioxid. Redox Signal","year":"2005"},{"key":"2025032719421400800_R28","first-page":"2382","article-title":"Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization","volume-title":"J. Clin. Invest.","year":"2005"},{"key":"2025032719421400800_R29","first-page":"395","article-title":"The IGF-1\/PI3K\/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors","volume-title":"Mol. Cell","year":"2004"},{"key":"2025032719421400800_R30","first-page":"119","article-title":"The forkhead transcription factor Foxo1 regulates adipocyte differentiation","volume-title":"Dev. Cell","year":"2003"},{"key":"2025032719421400800_R31","first-page":"2286","article-title":"Immunization enhances inflammation and tissue destruction in response to Porphyromonas gingivalis","volume-title":"Infect. Immun.","year":"2006"},{"key":"2025032719421400800_R32","first-page":"2997","article-title":"Diabetes alters the response to bacteria by enhancing fibroblast apoptosis","volume-title":"Endocrinology","year":"2004"},{"key":"2025032719421400800_R33","first-page":"510","article-title":"Diabetes enhances periodontal bone loss through enhanced resorption and diminished bone formation","volume-title":"J. Dent. Res.","year":"2006"},{"key":"2025032719421400800_R34","first-page":"345","article-title":"Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways","volume-title":"Bone","year":"2007"},{"key":"2025032719421400800_R35","first-page":"12096","article-title":"FOXO1 functions as a master switch that regulates gene expression necessary for tumor necrosis factor-induced fibroblast apoptosis","volume-title":"J. Biol. Chem.","year":"2005"},{"key":"2025032719421400800_R36","first-page":"12087","article-title":"Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways","volume-title":"J. Biol. Chem.","year":"2005"},{"key":"2025032719421400800_R37","first-page":"3164","article-title":"Mice laking monocyte chemoattractant protein 1 have enhanced susceptibility to an interstitial polymicrobial infection due to impaired moncyte recruitment","volume-title":"Infect. Immun.","year":"2002"},{"key":"2025032719421400800_R38","first-page":"S13","article-title":"The healing potential of the periosteum molecular aspects","volume-title":"Injury","year":"2005"},{"key":"2025032719421400800_R39","first-page":"C850","article-title":"Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor","volume-title":"Am. J. Physiol.","year":"2007"},{"key":"2025032719421400800_R40","first-page":"89","article-title":"The use of rodent models to investigate host-bacteria interactions related to periodontal diseases","volume-title":"J. Clin. Periodontol.","year":"2008"},{"key":"2025032719421400800_R41","first-page":"4158","article-title":"Bone resorption caused by three periodontal pathogens in vivo in mice is mediated in part by prostaglandin","volume-title":"Infect. Immun.","year":"1998"},{"key":"2025032719421400800_R42","first-page":"1630","article-title":"Mouse osteoblastic cells (MC3T3\u2013E1) at different stages of differentiation have opposite effects on osteoclastic cell formation","volume-title":"Endocrinology","year":"1991"},{"key":"2025032719421400800_R43","first-page":"1048","article-title":"Cytokine-induced nitric-oxide-dependent apoptosis in mouse osteoblastic cells: involvement of p38MAP kinase","volume-title":"Arch. Oral Biol.","year":"2006"},{"key":"2025032719421400800_R44","first-page":"749","article-title":"Interactions between immune and bone cells: new insights with many remaining questions","volume-title":"J. Clin. Invest.","year":"2000"},{"key":"2025032719421400800_R45","first-page":"785","article-title":"Induction of apoptosis in chondrocytes by tumor necrosis factor-\u03b1","volume-title":"J. Orthop. Res.","year":"2001"},{"key":"2025032719421400800_R46","first-page":"27298","article-title":"Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting \u03b2-catenin from T cell factor- to forkhead box O-mediated transcription","volume-title":"J. Biol. Chem.","year":"2007"},{"key":"2025032719421400800_R47","first-page":"279","article-title":"FoxO transcription factors in oxidative stress response and ageing: a new fork on the way to longevity?","volume-title":"Biol. Chem.","year":"2008"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/12\/8711\/62577207\/8244.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/12\/8711\/62577207\/8244.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T19:18:38Z","timestamp":1743362318000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/12\/8711\/8004711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12]]},"references-count":47,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2008,12,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.12.8711","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"type":"electronic","value":"1550-6606"},{"type":"print","value":"0022-1767"}],"subject":[],"published-other":{"date-parts":[[2008,12]]},"published":{"date-parts":[[2008,12]]}}}