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image of Clodronate: The Influence on ATP Purinergic Signaling

Abstract

ATP is involved in numerous physiological functions, such as neurotransmission, modulation, and secretion, as well as in cell proliferation, differentiation, and death. While ATP serves an essential intracellular role as a source of energy, it behaves differently in the extracellular environment, where it acts as a signaling molecule capable of activating specific purinergic receptors (P2YRs and P2XRs) that modulate the response to ATP. Extracellular ATP signaling is a dynamic area of research, with particular interest in ATP’s effects on inflammatory conditions and pain modulation. Clodronate differs from other bisphosphonates that contain an amino group in their structure (N-BPs), and it is metabolized within osteoclasts into a toxic ATP analog, AppCCl2p, which causes mitochondrial dysfunction and osteoclast apoptosis. This characteristic differentiates Clodronate from N-BPs, as the latter act by interfering with the mevalonate pathway. Clodronate has demonstrated anti-inflammatory and analgesic activity in various bone and musculoskeletal diseases through mechanisms involving macrophages, neutrophils, peripheral nociceptors, and the central nervous system.

ATP produced inside cells is accumulated within transport vesicles, where it penetrates a VNUT channel and is then released extracellularly, playing an active role in acute and chronic inflammatory processes, neurotransmission of pain, and liver disease regulation. Clodronate influences these processes due to its strong inhibitory effect on VNUT-mediated ATP release.

The aim of this review is to highlight the therapeutic potential offered by appropriate modulation of cellular ATP release and the inhibitory effects of Clodronate on the channel through which ATP penetrates transport vesicles.

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2025-01-03
2025-07-07

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References

  1. Burnstock G. Introduction to purinergic signaling. Methods Mol. Biol. 2020 2041 1 15 10.1007/978‑1‑4939‑9717‑6_1 31646477
    [Google Scholar]
  2. Ghildyal P. Manchanda R. Neurotransmission by ATP: New insights, novel mechanisms. Indian J. Biochem. Biophys. 2002 39 3 137 147 22905383
    [Google Scholar]
  3. Burnstock G. Purinergic signalling: Pathophysiology and therapeutic potential. Keio J. Med. 2013 62 3 63 73 10.2302/kjm.2013‑0003‑RE 24067872
    [Google Scholar]
  4. Pelleg A. Sirtori E. Rolland J.F. Mahadevan A. DT-0111: A novel P2X3 receptor antagonist. Purinergic Signal. 2023 19 3 467 479 10.1007/s11302‑023‑09930‑5 36944825
    [Google Scholar]
  5. Abbracchio M.P. Burnstock G. Verkhratsky A. Zimmermann H. Purinergic signalling in the nervous system: An overview. Trends Neurosci. 2009 32 1 19 29 10.1016/j.tins.2008.10.001 19008000
    [Google Scholar]
  6. Mahmood A. Iqbal J. Purinergic receptors modulators: An emerging pharmacological tool for disease management. Med. Res. Rev. 2022 42 4 1661 1703 10.1002/med.21888 35561109
    [Google Scholar]
  7. Oliveira Á. Illes P. Ulrich H. Purinergic receptors in embryonic and adult neurogenesis. Neuropharmacology 2016 104 272 281 10.1016/j.neuropharm.2015.10.008 26456352
    [Google Scholar]
  8. Burnstock G. Purine and purinergic receptors. Brain Neurosci. Adv. 2018 2 2398212818817494 10.1177/2398212818817494 32166165
    [Google Scholar]
  9. Haddad M. Cherchi F. Alsalem M. Al-saraireh Y.M. Madae’en S. Adenosine receptors as potential therapeutic analgesic targets. Int. J. Mol. Sci. 2023 24 17 13160 10.3390/ijms241713160 37685963
    [Google Scholar]
  10. Al-Aqtash R. Collier D.M. Ionotropic purinergic receptor 7 (P2X7) channel structure and pharmacology provides insight regarding non-nucleotide agonism. Channels (Austin) 2024 18 1 2355150 10.1080/19336950.2024.2355150 38762911
    [Google Scholar]
  11. Moriyama Y. Nomura M. Clodronate: A vesicular ATP release blocker. Trends Pharmacol. Sci. 2018 39 1 13 23 10.1016/j.tips.2017.10.007 29146440
    [Google Scholar]
  12. Russell R.G.G. Rogers M.J. Bisphosphonates: From the laboratory to the clinic and back again. Bone 1999 25 1 97 106 10.1016/S8756‑3282(99)00116‑7 10423031
    [Google Scholar]
  13. Reszka A.A. Rodan G.A. Mechanism of action of bisphosphonates. Curr. Osteoporos. Rep. 2003 1 2 45 52 10.1007/s11914‑003‑0008‑5 16036064
    [Google Scholar]
  14. Frediani B. Giusti A. Bianchi G. Dalle Carbonare L. Malavolta N. Cantarini L. Saviola G. Molfetta L. Clodronate in the management of different musculoskeletal conditions. Minerva Med. 2018 109 4 300 325 10.23736/S0026‑4806.18.05688‑4 29947493
    [Google Scholar]
  15. Saviola G. Abdi-Ali L. Comini L. Dalle-Carbonare L.G. Use of clodronate in the management of osteoarthritis: An update. J. Biol. Regul. Homeost. Agents 2019 33 5 1315 1320 31591875
    [Google Scholar]
  16. Frediani B. Toscano C. Falsetti P. Nicosia A. Pierguidi S. Migliore A. Giannotti S. Cantarini L. Conticini E. Intramuscular clodronate in long-term treatment of symptomatic knee osteoarthritis: A randomized controlled study. Drugs R D. 2020 20 1 39 45 10.1007/s40268‑020‑00294‑4 32078147
    [Google Scholar]
  17. Saviola G. Da Campo G. Bianchini M.C. Abdi-Ali L. Comini L. Rosini S. Molfetta L. Intra-articular clodronate in patients with knee osteoarthritis non-responder to intra-articular hyaluronic acid - A case report series of 9 patients with 8-month follow-up. Clin. Ter. 2023 174 3 245 248 10.7417/CT.2023.2528 37199358
    [Google Scholar]
  18. Okada S. Kiyama T. Sato E. Inhibition of phosphate transporters ameliorates the inflammatory and necrotic side effects of the nitrogen-containing bisphosphonate zoledronate in mice. Tohoku J. Exp. Med. 2013 231 2 145 158 10.1620/tjem.231.145
    [Google Scholar]
  19. Shima K. Nemoto W. Tsuchiya M. Tan-No K. Takano-Yamamoto T. Sugawara S. Endo Y. The bisphosphonates clodronate and etidronate exert analgesic effects by acting on glutamate- and/or ATP-related pain transmission pathways. Biol. Pharm. Bull. 2016 39 5 770 777 10.1248/bpb.b15‑00882 27150146
    [Google Scholar]
  20. McCloskey E. Paterson A.H. Powles T. Kanis J.A. Clodronate. Bone 2021 143 115715 10.1016/j.bone.2020.115715 33127577
    [Google Scholar]
  21. Thompson K. Rogers M.J. Coxon F.P. Crockett J.C. Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis. Mol. Pharmacol. 2006 69 5 1624 1632 10.1124/mol.105.020776 16501031
    [Google Scholar]
  22. Mass E. The stunning clodronate. J. Exp. Med. 2023 220 6 e20230339 10.1084/jem.20230339 36976179
    [Google Scholar]
  23. Spellberg B. Edwards J.E. Jr Type 1/type 2 immunity in infectious diseases. Clin. Infect. Dis. 2001 32 1 76 102 10.1086/317537 11118387
    [Google Scholar]
  24. Zhang X. Morrison D.C. Lipopolysaccharide-induced selective priming effects on tumor necrosis factor alpha and nitric oxide production in mouse peritoneal macrophages. J. Exp. Med. 1993 177 2 511 516 10.1084/jem.177.2.511 8426119
    [Google Scholar]
  25. Martinez F.O. Helming L. Gordon S. Alternative activation of macrophages: An immunologic functional perspective. Annu. Rev. Immunol. 2009 27 1 451 483 10.1146/annurev.immunol.021908.132532 19105661
    [Google Scholar]
  26. Rosini S. Saviola G. Comini L. Molfetta L. Mesenchymal cells are a promising -but still unsatisfying- anti- inflammatory therapeutic strategy for osteoarthritis: A narrative review. Curr. Rheumatol. Rev. 2023 19 3 287 293 10.2174/1573397118666220928141624 36173057
    [Google Scholar]
  27. Shapouri-Moghaddam A. Mohammadian S. Vazini H. Taghadosi M. Esmaeili S.A. Mardani F. Seifi B. Mohammadi A. Afshari J.T. Sahebkar A. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 2018 233 9 6425 6440 10.1002/jcp.26429 29319160
    [Google Scholar]
  28. Burnstock G. Purinergic signalling: Past, present and future. Braz. J. Med. Biol. Res. 2008 42 1 3 8 10.1590/S0100‑879X2008005000037 18853040
    [Google Scholar]
  29. Piccini A. Carta S. Tassi S. Lasiglié D. Fossati G. Rubartelli A. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way. Proc. Natl. Acad. Sci. USA 2008 105 23 8067 8072 10.1073/pnas.0709684105 18523012
    [Google Scholar]
  30. Corriden R Insel PA Basal release of ATP: An autocrine-paracrine mechanism for cell regulation. Science Signaling 2010 3 104 12 10.1126/scisignal.3104re1
    [Google Scholar]
  31. Sperlágh B. Haskó G. Németh Z. Vizi E.S. ATP released by LPS increases nitric oxideproduction in raw 264.7 macrophage cell line via P2ZP2X7 receptors. Neurochem. Int. 1998 33 3 209 215 10.1016/S0197‑0186(98)00025‑4 9759915
    [Google Scholar]
  32. Wang J. Takemura N. Saitoh T. Macrophage response driven by extracellular ATP. Biol. Pharm. Bull. 2021 44 5 599 604 10.1248/bpb.b20‑00831 33952816
    [Google Scholar]
  33. Kato Y. Ohsugi K. Fukuno Y. Iwatsuki K. Harada Y. Miyaji T. Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment. Proc. Natl. Acad. Sci. USA 2022 119 30 e2122158119 10.1073/pnas.2122158119 35858418
    [Google Scholar]
  34. Hagelauer N. Pabst A.M. Ziebart T. Ulbrich H. Walter C. in vitro effects of bisphosphonates on chemotaxis, phagocytosis, and oxidative burst of neutrophil granulocytes. Clin. Oral Investig. 2015 19 1 139 148 10.1007/s00784‑014‑1219‑0 24668343
    [Google Scholar]
  35. Hyvönen P.M. Kowolik M.J. Modification by clodronate and fluoride of hydroxyapatite-induced neutrophil chemiluminescence in vitro. J. Clin. Lab. Immunol. 1995 46 2 63 72 8789129
    [Google Scholar]
  36. Nussler A.K. Wittel U.A. Nussler N.C. Beger H.G. Leukocytes, the Janus cells in inflammatory disease. Langenbecks Arch. Surg. 1999 384 2 222 232 10.1007/s004230050196 10328179
    [Google Scholar]
  37. Malech H.L. DeLeo F.R. Quinn M.T. The role of neutrophils in the immune system: An overview. Methods Mol. Biol. 2020 2087 3 10 10.1007/978‑1‑0716‑0154‑9_1 31728979
    [Google Scholar]
  38. Harada Y. Kato Y. Miyaji T. Omote H. Moriyama Y. Hiasa M. Vesicular nucleotide transporter mediates ATP release and migration in neutrophils. J. Biol. Chem. 2018 293 10 3770 3779 10.1074/jbc.M117.810168 29363573
    [Google Scholar]
  39. Rosini S. Rosini S. Saviola G. Molfetta L. Adenosine triphosphate: A new player in complex regional pain syndrome type 1. Minerva Med. 2024 10.23736/S0026‑4806.24.09345‑5 39101383
    [Google Scholar]
  40. Kato Y. Hiasa M. Ichikawa R. Hasuzawa N. Kadowaki A. Iwatsuki K. Shima K. Endo Y. Kitahara Y. Inoue T. Nomura M. Omote H. Moriyama Y. Miyaji T. Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain. Proc. Natl. Acad. Sci. USA 2017 114 31 E6297 E6305 10.1073/pnas.1704847114 28720702
    [Google Scholar]
  41. Illes P. Ulrich H. Chen J.F. Tang Y. Purinergic receptors in cognitive disturbances. Neurobiol. Dis. 2023 185 106229 10.1016/j.nbd.2023.106229 37453562
    [Google Scholar]
  42. Kohno K. Tsuda M. Role of microglia and P2X4 receptors in chronic pain. Pain Rep. 2021 6 1 e864 10.1097/PR9.0000000000000864 33981920
    [Google Scholar]
  43. Kohno K. Shirasaka R. Yoshihara K. Mikuriya S. Tanaka K. Takanami K. Inoue K. Sakamoto H. Ohkawa Y. Masuda T. Tsuda M. A spinal microglia population involved in remitting and relapsing neuropathic pain. Science 2022 376 6588 86 90 10.1126/science.abf6805 35357926
    [Google Scholar]
  44. Inoue K. Microglia in neuropathic pain. Adv. Neurobiol. 2024 37 399 403 10.1007/978‑3‑031‑55529‑9_22 39207704
    [Google Scholar]
  45. Ulmann L. Hatcher J.P. Hughes J.P. Chaumont S. Green P.J. Conquet F. Buell G.N. Reeve A.J. Chessell I.P. Rassendren F. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J. Neurosci. 2008 28 44 11263 11268 10.1523/JNEUROSCI.2308‑08.2008 18971468
    [Google Scholar]
  46. Inoue K. Role of the P2X4 receptor in neuropathic pain. Curr. Opin. Pharmacol. 2019 47 33 39 10.1016/j.coph.2019.02.001 30878800
    [Google Scholar]
  47. Calovi S. Mut-Arbona P. Sperlágh B. Microglia and the purinergic signaling system. Neuroscience 2019 405 137 147 10.1016/j.neuroscience.2018.12.021 30582977
    [Google Scholar]
  48. Smith P.A. BDNF in neuropathic pain; The culprit that cannot be apprehended. Neuroscience 2024 543 49 64 10.1016/j.neuroscience.2024.02.020 38417539
    [Google Scholar]
  49. Klein K. Aeschlimann A. Jordan S. Gay R. Gay S. Sprott H. ATP induced brain-derived neurotrophic factor expression and release from osteoarthritis synovial fibroblasts is mediated by purinergic receptor P2X4. PLoS One 2012 7 5 e36693 10.1371/journal.pone.0036693 22715356
    [Google Scholar]
  50. Naviaux R.K. Metabolic features of the cell danger response. Mitochondrion 2014 16 7 17 10.1016/j.mito.2013.08.006 23981537
    [Google Scholar]
  51. Ye S.S. Tang Y. Song J.T. ATP and adenosine in the retina and retinal diseases. Front. Pharmacol. 2021 12 654445 10.3389/fphar.2021.654445 34211393
    [Google Scholar]
  52. Rawish E. Langer H.F. Platelets and the role of P2X receptors in nociception, pain, neuronal toxicity and thromboinflammation. Int. J. Mol. Sci. 2022 23 12 6585 10.3390/ijms23126585 35743029
    [Google Scholar]
  53. Inoue K. The role of ATP receptors in pain signaling. Neurochem. Res. 2022 47 9 2454 2468 10.1007/s11064‑021‑03516‑6 35094248
    [Google Scholar]
  54. Moehring F. Cowie A.M. Menzel A.D. Weyer A.D. Grzybowski M. Arzua T. Geurts A.M. Palygin O. Stucky C.L. Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling. eLife 2018 7 e31684 10.7554/eLife.31684 29336303
    [Google Scholar]
  55. Takahashi T. Kimura Y. Niwa K. Ohmiya Y. Fujimura T. Yamasaki K. Aiba S. in vivo imaging demonstrates ATP release from murine keratinocytes and its involvement in cutaneous inflammation after tape stripping. J. Invest. Dermatol. 2013 133 10 2407 2415 10.1038/jid.2013.163 23552799
    [Google Scholar]
  56. Ferrari D. Casciano F. Secchiero P. Reali E. Purinergic signaling and inflammasome activation in psoriasis pathogenesis. Int. J. Mol. Sci. 2021 22 17 9449 10.3390/ijms22179449 34502368
    [Google Scholar]
  57. Maruyama K. Takayama Y. Sugisawa E. Yamanoi Y. Yokawa T. Kondo T. Ishibashi K. Sahoo B.R. Takemura N. Mori Y. Kanemaru H. Kumagai Y. Martino M.M. Yoshioka Y. Nishijo H. Tanaka H. Sasaki A. Ohno N. Iwakura Y. Moriyama Y. Nomura M. Akira S. Tominaga M. The ATP transporter VNUT mediates induction of dectin-1-triggered candida nociception. iScience 2018 6 306 318 10.1016/j.isci.2018.08.007 30240621
    [Google Scholar]
  58. Hasuzawa N. Moriyama S. Moriyama Y. Nomura M. Physiopathological roles of vesicular nucleotide transporter (VNUT), an essential component for vesicular ATP release. Biochim. Biophys. Acta Biomembr. 2020 1862 12 183408 10.1016/j.bbamem.2020.183408 32652056
    [Google Scholar]
  59. Mizuhara M. Kometani-Gunjigake K. Nakao-Kuroishi K. Toyono T. Hitomi S. Morii A. Shiga M. Seta Y. Ono K. Kawamoto T. Vesicular nucleotide transporter mediates adenosine triphosphate release in compressed human periodontal ligament fibroblast cells and participates in tooth movement-induced nociception in rats. Arch. Oral Biol. 2020 110 104607 10.1016/j.archoralbio.2019.104607 31810015
    [Google Scholar]
  60. Hasuzawa N. Tatsushima K. Wang L. Kabashima M. Tokubuchi R. Nagayama A. Ashida K. Ogawa Y. Moriyama Y. Nomura M. Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury. Sci. Rep. 2021 11 1 5192 10.1038/s41598‑021‑83144‑w 33664289
    [Google Scholar]
  61. Burnstock G. Vaughn B. Robson S.C. Purinergic signalling in the liver in health and disease. Purinergic Signal. 2014 10 1 51 70 10.1007/s11302‑013‑9398‑8 24271096
    [Google Scholar]
  62. Vaughn B.P. Robson S.C. Burnstock G. Pathological roles of purinergic signaling in the liver. J. Hepatol. 2012 57 4 916 920 10.1016/j.jhep.2012.06.008 22709619
    [Google Scholar]
/content/journals/crr/10.2174/0115733971358895241216112008
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Clodronate: The Influence on ATP Purinergic Signaling
Bentham Science Publishers ; https://doi.org/10.2174/0115733971358895241216112008
/content/journals/crr/10.2174/0115733971358895241216112008
/content/journals/crr/10.2174/0115733971358895241216112008
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  • Article Type:     Review Article
Keywords: VNUT ; Clodronate ; ATP ; purinergic signaling receptor

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