RESUMO
The peroxisome proliferator-activated receptor gamma (PPARγ) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPARγ pro-adipocytic and insulin sensitizing activities, also determine PPARγ osteoblastic (pS112) and osteoclastic (pS273) activities. Treatment of either hyperglycemic or normoglycemic animals with SR10171, an inverse agonist that blocks pS273 but not pS112, increased trabecular and cortical bone while normalizing metabolic parameters. Additionally, SR10171 treatment modulated osteocyte, osteoblast, and osteoclast activities, and decreased marrow adiposity. These data demonstrate that regulation of bone mass and energy metabolism shares similar mechanisms suggesting that one pharmacologic agent could be developed to treat both diabetes and metabolic bone disease.
Assuntos
Reabsorção Óssea , Osteogênese , PPAR gama/metabolismo , Processamento de Proteína Pós-Traducional , Adipócitos/metabolismo , Animais , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/metabolismo , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , Mutação , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteócitos/metabolismo , Osteogênese/efeitos dos fármacos , PPAR alfa/metabolismo , PPAR gama/agonistas , PPAR gama/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Rosiglitazona , Tiazolidinedionas/farmacologia , Microtomografia por Raio-XRESUMO
A total synthesis of a structure proposed for himastatin was accomplished. The non-identity of the fully synthetic material with himastatin necessitated a revision of the assigned structure. Confirmation of the revised stereostructure was subsequently confirmed through total synthesis. Among the achievements during this effort were i) stereospecific routes to both anti-cis and syn-cis pyrrolindoline substructures; ii) a practical synthesis to 5-hydroxypiperazic acid in enantiomerically pure form; iii) a Stille coupling leading to a complex bi-indole moiety, and iv) efficient protecting group management throughout the evolving depsipeptide domain. The outlines for a biological pharmacophore have been delineated. The alternating D- and L-substituents in the 6-mer as well as the biaryl linkage connecting the two identical subunits are critical for maintaining biological activity. This pattern is simulated in another antibiotic, and suggests a possible structural trend for future SAR investigations.
