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T and B cell Mediated Bone Resorption through RANK-RANK-L Activation in Periodontal Disease. Part II

Prelude:When I posted the first part of this review I was asked by one of the reader " how did this post help general dentist in their practice". This made me realize that I should probably add a prelude to my post explaining the practical relevance of the post below, and that would make sense and create interest to those who read.
I posted this paper to highlight the fact that how the chronic inflammation in periodontal disease plays part in the bone loss. Its of importance that this inflammation of periodontium be contained and be treated properly( surgical or nonsurgical treatment) to not only limit the local but also the systemic manifestation that it could have. The local inflammation could have a systemic affect by triggering the immune response or through the up regulation of the cytokine levels. The recent paper in NEMJ by Tonneti et. al (March 2007) also highlights this relationship.


T Cells In Periodontal Bone Loss:

It has been shown that T cells can directly induce bone loss via RANK-L dependent osteoclast or indirectly through production of pro-inflammatory cytokines like IL-1 and TNF- α, which lead to expression of RANK-L on osteoblasts.

(a) Indirect mechanism: (fig 1) (10)


The periodontal tissue harbors Th1 and Th2 cells. A progressive periodontal pocket is dominated by gram-negative bacteria which produces lipopolysaccharides (LPS). The LPS is the antigenic stimulus for the T cell production of INF-γ and B7 stimulation. The B7 stimulated Th1 cells along with INF-γ counter-stimulate macrophages to secrete bone resorption-inductive cytokines, such as IL-1 and TNF-α (3). It has been demonstrated that Th1 and not Th2-type cells could trigger periodontal bone resorption. IL-4 and IL10 produced by the Th2 type cells inhibit the induction of IL-1 and TNF-α production by LPS plus IFN-γ. In the presence of periodontal infection, the LPS produced by the gram negative bacteria cause a shift towards the Th1 polarization, which then causes the bone resorption in periodontal disease (3). This was seen in a rowett strain rat model where gingival injection of specific antigen (A. actinomycetemcomitans outer membrane protein) and LPS induced local bone resorption after the transfer of Th1 clone cells but no resorption after transfer of Th2 clone cells using TRAP staining to identify osteoclasts in alveolar bone.

(b) Direct mechanism: (fig 2) (9)


The very first evidence of the linkage between the T cells expressed RANK-L and bone loss was seen in an animal arthritis model (5) and was also demonstrated in activated human T cells(6). The activated T cells were seen to produce RANK-L which induced osteoclastogenesis and IFN-γ is found to suppress osteoclastogenesis by inhibiting the RANK-RANK-L pathway.

The RANK–RANK-L interaction activates the essential signaling for osteoclastogenesis through the up-regulation of TRAF6 (tumor necrosis factor receptor associated factor 6), c-Fos and calcium pathways. Nuclear factor of activated T cells c1 (NFATc1) which is a member of the NFAT family of transcription factor genes integrates the above three pathways for osteoclast differentiation (9). IFN-γ induced rapid degradation of the RANK-L adapter protein, TRAF6, which resulted in the inhibition of the RANK-L induced activation of the transcription factor NF-κB and Jun N-terminal kinase (JNK) (8).

T cells have been show to directly induce differentiation of osteoclast precursors into osteoclasts by binding to RANK-L receptors in adherent peripheral blood mononuclear cells (PMBCs) both in patients with rheumatoid arthritis and in periodontitis patients. To determine that activated human T cells directly induce osteoclastogenesis from human monocytes, PMBC were cultured with M-CSF for 3 days and for further 7 days with activated CD3+ T cells. Immunohistochemistry analysis revealed that osteoclasts were formed even in absence of exogenous sRANKL and that this osteoclast formation was inhibited by adding OPG (6). In another in-vitro model it was seen that the osteoclasts spontaneously developed in a T cell dependent manner from unfractioned PBMCs of periodontitis patients as compared to the PBMCs from periodontally healthy patients which required additional stimulus from RANK-L and macrophage colony stimulating factor (MCSF). Also, the unfractioned PMBCs from periodontitis patients show overexpression of RANKL and TNF-α which was measured using reverse transcription-polymerase chain rection. The use of anti-RANKL and anti-TNF-α antibodies significantly decreased osteoclastogenesis (7). The peripheral blood T and B cells from periodontitis patients when stimulated with oral bacterium (A. actinomycetemcomitans) produced both the sRANKL and cellular RANKL (2). These data show that the bone loss in periodontal disease via T cell is by both the RANK-L dependent direct and indirect mechanisms.

B Cells In Periodontal Bone Loss:

Earlier histological studies had established that a chronic progressive lesion was associated with increased infiltration of B cells and plasma cells. It is now established through rat and human periodontitis models that B cells do play an equal if not a greater role in the bone resorption. Initial evidence of B cell involvement was seen when cultured B cells and CD4+ T cells but not CD8+ T cells showed RANK-L mediated bone resorption.

Activated B cells not only supported osteoclast differentiation in the absence of sRANKL, but also increased osteoclast differentiation/activation in the presence of sRANKL(1). The above results were confirmed in congenitally athymic rats which had deficient T cell-B cell function. When these rats received Ag specific RANK-L expressing B cells, they showed increased osteoclast formation and periodontal bone loss, also pointing to the fact that Ag-specific RANK-L expressing B cells can induce bone loss in the absence of T cells. The Ag-responsive B cells may lead to an enhancement of the induction of osteoclast differentiation (4). A study in gingival tissue of periodontitis patients demonstrated that the percentage of RANKL positive T cells (50-60%) was substantially less than the percentage of RANKL positive B cells ( >90%).It also showed that although most B cells were positive for RANKL, not all T cells expressed RANKL in diseased gingival tissue where as very few lymphocytes expressed RANKL in healthy tissue when observed with double-color confocal microscopy (2). B cells secrete high levels of IL10 and IFN-γ which are inhibitory cytokines but these seemed to be overwhelmed by stimulatory factors such as macrophage inflammatory protein-alpha (MIP-α), monocyte chemotactic protein-3 (MCP-3), and macrophage colony stimulating factor (M-CSF) (1). Although it has been demonstrated both in vitro and in vivo that activated B cells enhance osteoclastogenesis and bone resorption it is still inconclusive if B cells can contribute more extensively to bone resorption than T cells.

Conclusion and future directions:

With the basic understanding of the interplay of the immune cells and cytokines in the process of bone resorption, the future certainly seems interesting as these data would help to develop strategies to treat inflammatory periodontal disease and other systemic disease associated with bone loss. At the molecular levels the possible targets for pharmacological intervention would most likely be the TRAF6 or the Ca++ signaling pathway which could lead to suppression of the osteoclastogenesis by acting on NFATc1. Specifically potassium channel blockers to block the calcium signaling are been investigated as the potential therapeutic approach to reduce RANKL expression. The other potential therapeutic approach would be to modulate expression of cytokines and their receptors using techniques like gene therapy to reduce IL-1 or TNF-α production. In periodontitis host modulation using chemically modified tetracycline (CMT) has shown to reduce the periodontal disease by suppression of matrix metalloproteinases (MMP) activity. In fact CMTs are now been studied for effects on rheumatoid arthritis and osteoarthritis. More studies should be directed towards the interplay of the T cells and the B cells in periodontal disease and for the development of new strategies for inhibition of bone destruction in this disease.

References:

1. Choi Y, Woo K M, Ko S H et al. Osteoclastogenesis is enhanced by activated B cells but suppressed by activated CD8+ T cells. Eur. J. Immunol; 2001: 2179-2188.

2. Kawai T, Matsuyama T, Hososkawa Y et al. B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease. Am J Pathol: 2006, 169:987-998.

3. Kawai T, Eisen-Lev R, Seki M, et al. Requirement B7 costimulation for Th1-mediated inflammatory bone resorption in experimental periodontal disease. The Journal of Immunology; 2006, 164:2102-2109.

4. Han X, Kawai T, Eastcott J. W, Taubman M A,. Bacterial-responsive B lymphocytes induce periodontal bone resorption. The Journal of Immunology; 2006, 176:625-631.

5. Kong Y, Feige U, Sarosi L et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature; 1999, 402:304-309.

6. Kotake S, Udagawa N, Hakoda M et al. Activated human T cells directly induce osteoclastogenesis from human monocytes. Arth and Rheum; 2001, 44: 1003-1012.

7. Brunetti G, Colucci S, Pignataro P et al. J periodontal; 2005, 76:1675-1680.

8. Takayanagi H, Ogasawara K, Hida S et al. T cell mediated regulation of osteoclastogenesis by signaling cross-talk between RANKL and IFN-γ. Nature; 2000, 408:600-605.

9. Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodont Res; 2005, 40:287-293.

10. Taubman M.A., Kawai T. Involvement of T lymphocytes in periodontal disease and in direct and indirect induction of bone resorption. Crit rev Oral Bio Med; 2001, 12(2): 125-135.

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