title: The transition state analog inhibitor of Purine Nucleoside Phosphorylase (PNP) Immucillin-H arrests bone loss in rat periodontal disease models.
abstract: Purine nucleoside phosphorylase (PNP) is a purine-metabolizing enzyme that catalyzes the reversible phosphorolysis of 6-oxypurine (deoxy)nucleosides to their respective bases and (deoxy)ribose-1-phosphate. It is a key enzyme in the purine salvage pathway of mammalian cells. The present investigation sought to determine whether the PNP transition state analog inhibitor (Immucillin-H) arrests bone loss in two models of induced periodontal disease in rats. Periodontal disease was induced in rats using ligature or LPS injection followed by administration of Immucillin-H for direct analysis of bone loss, histology and TRAP staining. In vitro osteoclast differentiation and activation of T CD4+ cells in the presence of Immucillin-H were carried out for assessment of RANKL expression, PNP and Cathepsin K activity. Immucillin-H inhibited bone loss induced by ligatures and LPS, leading to a reduced number of infiltrating osteoclasts and inflammatory cells. In vitro assays revealed that Immucillin-H could not directly abrogate differentiation of osteoclast precursor cells, but affected lymphocyte-mediated osteoclastogenesis. On the other hand, incubation of pre-activated T CD4+ with Immucillin-H decreased RANKL secretion with no compromise of cell viability. The PNP transition state analog Immucillin-H arrests bone loss mediated by T CD4+ cells with no direct effect on osteoclasts. PNP inhibitor may have an impact in the treatment of diseases characterized by the presence of pathogens and imbalances of bone metabolism.
authors.affiliation: Graduate Program in Cellular and Molecular Biology, Centro de Pesquisas/ Biologia Molecular e Funcional (CP-BMF), Pontifícia Universidade Católica do Rio Grande do Sul-PUCRS, RS, Brazil.
authors.forename: Candida
authors.initials: C
authors.lastname: Deves
authors.forename: Thiago Milech
authors.initials: TM
authors.lastname: de Assunção
authors.forename: Rodrigo Gay
authors.initials: RG
authors.lastname: Ducati
authors.forename: Maria Martha
authors.initials: MM
authors.lastname: Campos
authors.forename: Luiz Augusto
authors.initials: LA
authors.lastname: Basso
authors.forename: Diogenes Santiago
authors.initials: DS
authors.lastname: Santos
authors.forename: Eraldo L
authors.initials: EL
authors.lastname: Batista
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D010510:Periodontal Diseases / Q000517:prevention & control*; D011684:Purine Nucleosides / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine; D011683:Purine-Nucleoside Phosphorylase