Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor-{alpha} and interleukin-1{beta}, but suppresses that by interleukin-17A. Importance of proteolytic degradation of osteoprotegerin by lysine gingipain [Cell Biology]

April 22nd, 2014 by Akiyama, T., Miyamoto, Y., Yoshimura, K., Yamada, A., Takami, M., Suzawa, T., Hoshino, M., Imamura, T., Akiyama, C., Yasuhara, R., Mishima, K., Maruyama, T., Kohda, C., Tanaka, K., Potempa, J., Yasuda, H., Baba, K., Kamijo, R.

Periodontitis is a chronic inflammatory disease accompanied by alveolar bone resorption by osteoclasts. Porphyromonas gingivalis, an etiological agent for periodontitis, produces cysteine proteases called gingipains, which are classified based on their cleavage site specificity, i.e., arginine (Rgps) and lysine (Kgps) gingipains. We previously reported that Kgp degraded osteoprotegerin (OPG), an osteoclastogenesis inhibitory factor secreted by osteoblasts, and enhanced osteoclastogenesis induced by various Toll-like receptor (TLR) ligands (Yasuhara R, et al. Biochem J, 419, 159-166, 2009). Osteoclastogenesis is induced not only by TLR ligands but also by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-17A, in inflammatory conditions such as periodontitis. Although Kgp augmented osteoclastogenesis induced by TNF-α and IL-1β in co-cultures of mouse osteoblasts and bone marrow cells, it suppressed that induced by IL-17A. In a comparison of proteolytic degradation of these cytokines by Kgp in a cell-free system with that of OPG, TNF-α and IL-1β were less susceptible, while IL-17A and OPG were equally susceptible to degradation by Kgp. These results indicate that the enhancing effect of Kgp on cytokine-induced osteoclastogenesis is dependent on the difference in degradation efficiency between each cytokine and OPG. In addition, elucidation of the N-Terminal amino acid sequences of OPG fragments revealed that Kgp primarily cleaved OPG in its death domain homologous region, which might prevent dimer formation of OPG required for inhibition of RANKL. Collectively, our results suggest that degradation of OPG by Kgp is a crucial event in development of osteoclastogenesis and bone loss in periodontitis.
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