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Potassium Channel-blockers as Therapeutic Agents to Interfere with Bone Resorption of Periodontal Disease

¹ Tufts University School of Dental Medicine, One Kneeland Street, Boston, MA 02111, USA; and
² Department of Immunology, The Forsyth Institute, Boston, MA, USA;

View larger version (30K): [in this window] [in a new window]   Figure 1. Involvement of activated lymphocytes and macrophages in bone remodeling. Chronically activated T-cells produce RANKL that directly induces osteoclastogenesis and bone resorption in the presence of permissive factor MCSF. The soluble decoy receptor OPG blocks RANK-RANKL interactions. Activated T-cells also produce certain cytokines (TNF-, IL-11, and IL-17) that induce RANKL expression on osteoblasts/stromal cells, and other factors (IFN-, IL-10, IL-4, IL-3, TRAIL) that inhibit osteoclastogenesis. With a second signal from LPS, IFN- induces the expression of TNF-, IL-1, or IL-6 by macrophages. Activated B-cells express RANKL and can activate or inhibit osteoclastogenesis, depending on whether they are stimulated in the presence of Th2-like or Th1-like cytokines, respectively.

View larger version (40K): [in this window] [in a new window]   Figure 2. Up-regulation in the RANKL-to-OPG ratio correlates with increased Kv1.3 expression in patients with chronic periodontitis. Mononuclear infiltrates from healthy gingival or diseased gingival tissue from patients with chronic periodontitis (samples 1 to 3) were used to extract total RNA as described (Valverde et al., 2004). RT-PCR analyses were performed to amplify Kv1.3, IKCa1, RANKL, and OPG. Kv1.1 expression was undetectable in these samples (data not shown). Expression of GAPDH was used as a loading control, and PCR reactions for the intron-less coding sequence gene MC1R were performed to confirm the absence of genomic contamination (data not shown).

View larger version (38K): [in this window] [in a new window]   Figure 3. Roles of Kv1.3 and IKCa1 in T-cells and T-cell-mediated events. Kv1.3 and IKCa1 are expressed in T-cells and mediate a variety of functions upon T-cell activation, including setting resting membrane potential, modulation of Ca2+ influx, production of cytokines, and T-cell proliferation. Some of the cytokines produced by activated T-cells inhibit osteoclastogenesis and bone resorption, while others activate these processes. Other cytokines of the TNF-related family are involved in AICD of T-cells, B-cell co-stimulation, DC activation, and differentiation or inhibition of osteoclastogenesis. Administration of K+ channel-blockers may potentially inhibit the production of some of the cytokines that induce osteoclastogenesis in a RANK-dependent fashion, as well as cytokines that mediate their osteoclastogenic effects through a RANK/RANKL-independent pathway. Furthermore, Kv1.3 directly interacts with β1-integrin, and therefore its blockade might potentially regulate receptor independent β1-integrin-adhesion and migration functions.

Journal of Dental Research, Vol. 84, No. 6, 488-499 (2005)
DOI: 10.1177/154405910508400603


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