Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease.
Inflammatory lesions of periodontal disease contain all the cellular components, including abundant activated/memory T- and B-cells, necessary to control immunological interactive networks and to accelerate bone resorption by RANKL-dependent and -independent mechanisms. Blockade of RANKL function has been shown to ameliorate periodontal bone resorption and other osteopenic disorders without affecting inflammation. Development of therapies aimed at decreasing the expression of RANKL and pro-inflammatory cytokines by T-cells constitutes a promising strategy to ameliorate not only bone resorption, but also inflammation. Several reports have demonstrated that the potassium channels Kv1.3 and IKCa1, through the use of selective blockers, play important roles in T-cell-mediated events, including T-cell proliferation and the production of pro-inflammatory cytokines. More recently, a potassium channel-blocker for Kv1.3 has been shown to down-regulate bone resorption by decreasing the ratio of RANKL-to-OPG expression by memory-activated T-cells. In this article, we first summarize the mechanisms by which chronically activated/memory T-cells, in concert with B-cells and macrophages, trigger inflammatory bone resorption. Then, we describe the main structural and functional characteristics of potassium channels Kv1.3 and IKCa1 in some of the cells implicated in periodontal disease progression. Finally, this review elucidates some recent advances in the use of potassium channel-blockers of Kv1.3 and IKCa1 to ameliorate the clinical signs or side-effects of several immunological disorders and to decrease inflammatory bone resorption in periodontal disease.


BACKGROUND
AICD, activation-induced cell death; APC, antigen-presenting cells; B(K), large conductance; CRAC, calcium release-activated calcium channels; DC, dendritic cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IFN-gamma, interferon-gamma; IP(3), inositol (1,4,5)-triphosphate; (K)ir, inward rectifier; JNK, c-Jun N-terminal kinase; I(K), intermediate conductance; LPS, lipopolysaccharide; L, ligand; MCSF, macrophage colony-stimulating factor; MHC, major histocompatibility complex; NFAT, nuclear factor of activated T-cells; RANK, receptor activator of nuclear factor-kappaB; T(CM), central memory T-cells; T(EM), effector memory T-cells; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; OPG, osteoprotegerin; Omp29, 29-kDa outer membrane protein; PKC, protein kinase C; PLC, phospholipase C; RT-PCR, reverse-transcriptase polymerase chain-reaction; S(K), small conductance; TCR, T-cell receptor; and (K)v, voltage-gated.
Valverde
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P
Tufts University School of Dental Medicine, One Kneeland Street, Boston, MA 02111, USA. paloma.valverde@tufts.edu
Kawai
T
T
Taubman
M A
MA
D016301:Alveolar Bone Loss / Q000276:immunology / Q000517:prevention & control*; D001862:Bone Resorption / Q000276:immunology / Q000517:prevention & control; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051664:Kv1.3 Potassium Channel; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D010510:Periodontal Diseases / Q000276:immunology / Q000517:prevention & control; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D015221:Potassium Channels / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D002352:Carrier Proteins; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496973:KCNA3 protein, human; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel; D008024:Ligands; D008562:Membrane Glycoproteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha