Elucidation for anti-apoptotic action of tetrahydrobiopterin in osteoblastic cells

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We investigated the effects of 5, 6, 7, 8-tetrahydrobiopterin (BH4), a cofactor for nitric oxide (NO) synthase, on NO toxicity in mouse osteoblastic cell line MC3T3-E1 cells. 1) Proinflammatory cytokine mixture (TNF-α, IL-1β, and IFN-γ) and SNAP, an NO generator, decreased cell viability, but sepiapterin, which was converted intracellularly to BH4, increased it. Flow cytometric analysis showed that the reduction of cell viability by cytokines may be based upon cell death by apoptosis, but not lytic death as in necrosis. 2) Cytokine treatment caused the production of BH4. 3) In the presence of BH4, cytokines resulted in a statistically pronounced reduction (*p<0.05) in the amount of DNA fragmentation. These results suggest that the apoptotic cell death in response to cytokines is ascribed to NO and is protective by BH4. BH4 may act as the counterpart and counterbalance to NO-toxicity in MC3T3-E1 cells. 4) Actinobacillus actinomycetemcomitans (AA) has been implicated in the etiology of localized juvenile periodontitis (LJP) and the capsular-like polysaccharide antigen (CPA) from AA, is a potent mediator of bone resorption. CPA contains a potent antiproliferative polysaccharide whose activity is associated with apoptotic cell death in mouse MC3T3-E1 and human osteosarcoma, suggesting that apoptotic cell death in osteoblastic cells is associated with the pathogenesis of LJP. The elucidation of apoptotic mechanism may provide the therapeutic potential information for LJP.