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The purinergic receptor P2X5 contributes to bone loss in experimental periodontitis

  • Kim, Hyunsoo (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine) ;
  • Kajikawa, Tetsuhiro (Department of Microbiology, Penn Dental Medicine, University of Pennsylvania) ;
  • Walsh, Matthew C. (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine) ;
  • Takegahara, Noriko (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine) ;
  • Jeong, Yun Hee (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine) ;
  • Hajishengallis, George (Department of Microbiology, Penn Dental Medicine, University of Pennsylvania) ;
  • Choi, Yongwon (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine)
  • Received : 2018.06.14
  • Accepted : 2018.08.07
  • Published : 2018.09.30

Abstract

Purinergic receptor signaling is increasingly recognized as an important regulator of inflammation. The P2X family purinergic receptors P2X5 and P2X7 have both been implicated in bone biology, and it has been suggested recently that P2X5 may be a significant regulator of inflammatory bone loss. However, a role for P2X5 in periodontitis is unknown. The present study aimed to evaluate the functional role of P2X5 in ligature-induced periodontitis in mice. Five days after placement of ligature, analysis of alveolar bone revealed decreased bone loss in $P2rx5^{-/-}$ mice compared to $P2rx7^{-/-}$ and WT control mice. Gene expression analysis of the gingival tissue of ligated mice showed that IL1b, IL6, IL17a and Tnfsf11 expression levels were significantly reduced in $P2rx5^{-/-}$ compared to WT mice. These results suggest the P2X5 receptor may regulate bone loss related to periodontitis and it may thus be a novel therapeutic target in this oral disease.

Keywords

References

  1. Frencken JE, Sharma P, Stenhouse L, Green D, Laverty D and Dietrich T (2017) Global epidemiology of dental caries and severe periodontitis - a comprehensive review. J Clin Periodontol 44 Suppl 18, S94-S105 https://doi.org/10.1111/jcpe.12677
  2. Hajishengallis G (2014) Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response. Trends Immunol 35, 3-11 https://doi.org/10.1016/j.it.2013.09.001
  3. Hajishengallis G (2015) Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol 15, 30-44 https://doi.org/10.1038/nri3785
  4. Zenobia C, Hasturk H, Nguyen D, Van Dyke TE, Kantarci A and Darveau RP (2014) Porphyromonas gingivalis lipid A phosphatase activity is critical for colonization and increasing the commensal load in the rabbit ligature model. Infect Immun 82, 650-659 https://doi.org/10.1128/IAI.01136-13
  5. Thunell DH, Tymkiw KD, Johnson GK et al (2010) A multiplex immunoassay demonstrates reductions in gingival crevicular fluid cytokines following initial periodontal therapy. J Periodontal Res 45, 148-152 https://doi.org/10.1111/j.1600-0765.2009.01204.x
  6. Fujita Y, Ito H, Sekino S and Numabe Y (2012) Correlations between pentraxin 3 or cytokine levels in gingival crevicular fluid and clinical parameters of chronic periodontitis. Odontology 100, 215-221 https://doi.org/10.1007/s10266-011-0042-1
  7. Belibasakis GN and Bostanci N (2012) The RANKL-OPG system in clinical periodontology. J Clin Periodontol 39, 239-248 https://doi.org/10.1111/j.1600-051X.2011.01810.x
  8. Veldhoen M (2017) Interleukin 17 is a chief orchestrator of immunity. Nat Immunol 18, 612-621 https://doi.org/10.1038/ni.3742
  9. Walsh MC, Kim N, Kadono Y et al (2006) Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol 24, 33-63 https://doi.org/10.1146/annurev.immunol.24.021605.090646
  10. Burnstock G and Di Virgilio F (2013) Purinergic signalling and cancer. Purinergic Signal 9, 491-540 https://doi.org/10.1007/s11302-013-9372-5
  11. Franke H, Verkhratsky A, Burnstock G and Illes P (2012) Pathophysiology of astroglial purinergic signalling. Purinergic Signal 8, 629-657 https://doi.org/10.1007/s11302-012-9300-0
  12. Burnstock G and Williams M (2000) P2 purinergic receptors: modulation of cell function and therapeutic potential. J Pharmacol Exp Ther 295, 862-869
  13. Orriss IR, Key ML, Brandao-Burch A, Patel JJ, Burnstock G and Arnett TR (2012) The regulation of osteoblast function and bone mineralisation by extracellular nucleotides: The role of p2x receptors. Bone 51, 389-400 https://doi.org/10.1016/j.bone.2012.06.013
  14. Su X, Floyd DH, Hughes A et al (2012) The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling. J Clin Invest 122, 3579-3592 https://doi.org/10.1172/JCI38576
  15. Gartland A, Skarratt KK, Hocking LJ et al (2012) Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women. Eur J Hum Genet 20, 559-564 https://doi.org/10.1038/ejhg.2011.245
  16. Gartland A, Buckley KA, Hipskind RA et al (2003) Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice. Crit Rev Eukaryot Gene Expr 13, 243-253
  17. Ke HZ, Qi H, Weidema AF et al (2003) Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. Mol Endocrinol 17, 1356-1367 https://doi.org/10.1210/me.2003-0021
  18. Kim H, Walsh MC, Takegahara N et al (2017) The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts. Sci Rep 7, 196 https://doi.org/10.1038/s41598-017-00139-2
  19. Qu C, Bonar SL, Hickman-Brecks CL et al (2015) NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms. FASEB J 29, 1269-1279 https://doi.org/10.1096/fj.14-264804
  20. Ramos-Junior ES, Morandini AC, Almeida-da-Silva CL et al (2015) A Dual Role for P2X7 Receptor during Porphyromonas gingivalis Infection. J Dent Res 94, 1233-1242 https://doi.org/10.1177/0022034515593465
  21. Lister MF, Sharkey J, Sawatzky DA et al (2007) The role of the purinergic P2X7 receptor in inflammation. J Inflamm (Lond) 4, 5 https://doi.org/10.1186/1476-9255-4-5
  22. Franco C, Patricia HR, Timo S, Claudia B and Marcela H (2017) Matrix Metalloproteinases as Regulators of Periodontal Inflammation. Int J Mol Sci 18, 440 https://doi.org/10.3390/ijms18020440
  23. Eskan MA, Jotwani R, Abe T et al (2012) The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol 13, 465-473 https://doi.org/10.1038/ni.2260
  24. Assuma R, Oates T, Cochran D, Amar S and Graves DT (1998) IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immunol 160, 403-409
  25. Abe T and Hajishengallis G (2013) Optimization of the ligature-induced periodontitis model in mice. J Immunol Methods 394, 49-54 https://doi.org/10.1016/j.jim.2013.05.002
  26. Stutz A, Golenbock DT and Latz E (2009) Inflammasomes: too big to miss. J Clin Invest 119, 3502-3511 https://doi.org/10.1172/JCI40599
  27. Jacob F, Perez Novo C, Bachert C and Van Crombruggen K (2013) Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal 9, 285-306 https://doi.org/10.1007/s11302-013-9357-4
  28. Dutzan N, Konkel JE, Greenwell-Wild T and Moutsopoulos NM (2016) Characterization of the human immune cell network at the gingival barrier. Mucosal Immunol 9, 1163-1172 https://doi.org/10.1038/mi.2015.136
  29. Hajishengallis G, Moutsopoulos NM, Hajishengallis E and Chavakis T (2016) Immune and regulatory functions of neutrophils in inflammatory bone loss. Semin Immunol 28, 146-158 https://doi.org/10.1016/j.smim.2016.02.002
  30. Dutzan N, Abusleme L, Bridgeman H et al (2017) On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier. Immunity 46, 133-147 https://doi.org/10.1016/j.immuni.2016.12.010
  31. Kotake S, Udagawa N, Takahashi N et al (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103, 1345-1352 https://doi.org/10.1172/JCI5703
  32. Shahrara S, Pickens SR, Dorfleutner A and Pope RM (2009) IL-17 induces monocyte migration in rheumatoid arthritis. J Immunol 182, 3884-3891 https://doi.org/10.4049/jimmunol.0802246
  33. Robaszkiewicz A, Qu C, Wisnik E et al (2016) ARTD1 regulates osteoclastogenesis and bone homeostasis by dampening NF-kappaB-dependent transcription of IL-1beta. Sci Rep 6, 21131 https://doi.org/10.1038/srep21131
  34. Mariathasan S, Weiss DS, Newton K et al (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228-232 https://doi.org/10.1038/nature04515
  35. Wei S, Kitaura H, Zhou P, Ross FP and Teitelbaum SL (2005) IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115, 282-290 https://doi.org/10.1172/JCI200523394
  36. Takegahara N, Kim H, Mizuno H et al (2016) Involvement of Receptor Activator of Nuclear Factor-kappaB Ligand (RANKL)-induced Incomplete Cytokinesis in the Polyploidization of Osteoclasts. J Biol Chem 291, 3439-3454 https://doi.org/10.1074/jbc.M115.677427
  37. Kim H, Choi HK, Shin JH et al (2009) Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice. J Clin Invest 119, 813-825 https://doi.org/10.1172/JCI36809
  38. Kim H, Kim T, Jeong BC et al (2013) Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation. Cell Metab 17, 249-260 https://doi.org/10.1016/j.cmet.2013.01.002
  39. Song H, Kim H, Lee K et al (2012) Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice. EMBO J 31, 1147-1159 https://doi.org/10.1038/emboj.2011.480

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