RESUMEN
Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease destroying articular cartilage and bone. The female preponderance and the influence of reproductive states in RA have long linked this disease to sexually dimorphic, reproductive hormones such as prolactin (PRL). PRL has immune-enhancing properties and increases in the circulation of some patients with RA. However, PRL also suppresses the immune system, stimulates the formation and survival of joint tissues, acquires antiangiogenic properties upon its cleavage to vasoinhibins, and protects against joint destruction and inflammation in the adjuvant-induced model of RA. This review addresses risk factors for RA linked to PRL, the effects of PRL and vasoinhibins on joint tissues, blood vessels, and immune cells, and the clinical and experimental data associating PRL with RA. This information provides important insights into the pathophysiology of RA and highlights protective actions of the PRL/vasoinhibin axis that could lead to therapeutic benefits.
Asunto(s)
Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Cartílago Articular/patología , Inflamación/patología , Articulaciones/patología , Prolactina/inmunología , Inhibidores de la Angiogénesis/inmunología , Animales , Artritis Reumatoide/epidemiología , Artritis Reumatoide/fisiopatología , Cartílago Articular/irrigación sanguínea , Cartílago Articular/inmunología , Cartílago Articular/fisiopatología , Femenino , Humanos , Tolerancia Inmunológica , Inmunidad Celular , Inflamación/epidemiología , Inflamación/inmunología , Inflamación/fisiopatología , Articulaciones/irrigación sanguínea , Articulaciones/inmunología , Articulaciones/fisiopatología , Masculino , Reproducción , Factores Sexuales , Estrés Fisiológico , Estrés PsicológicoRESUMEN
The present research aimed to isolate the non-polar secondary metabolites that produce the vasodilator effects induced by the dichloromethane extract of Prunus serotina (P. serotina) fruits and to determine whether the NO/cGMP and the H2S/KATP channel pathways are involved in their mechanism of action. A bioactivity-directed fractionation of the dichloromethane extract of P. serotina fruits led to the isolation of ursolic acid and uvaol as the main non-polar vasodilator compounds. These compounds showed significant relaxant effect on rat aortic rings in an endothelium- and concentration-dependent manner, which was inhibited by NG-nitro-L-arginine methyl ester (L-NAME), DL-propargylglycine (PAG) and glibenclamide (Gli). Additionally, both triterpenes increased NO and H2S production in aortic tissue. Molecular docking studies showed that ursolic acid and uvaol are able to bind to endothelial NOS and CSE with high affinity for residues that form the oligomeric interface of both enzymes. These results suggest that the vasodilator effect produced by ursolic acid and uvaol contained in P. serotina fruits, involves activation of the NO/cGMP and H2S/KATP channel pathways, possibly through direct activation of NOS and CSE.
Asunto(s)
Sulfuro de Hidrógeno/agonistas , Óxido Nítrico/agonistas , Prunus avium/química , Triterpenos/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Alquinos/antagonistas & inhibidores , Alquinos/farmacología , Animales , Aorta/citología , Aorta/efectos de los fármacos , Aorta/metabolismo , GMP Cíclico/metabolismo , Cistationina gamma-Liasa/química , Cistationina gamma-Liasa/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Frutas/química , Gliburida/antagonistas & inhibidores , Gliburida/farmacología , Glicina/análogos & derivados , Glicina/antagonistas & inhibidores , Glicina/farmacología , Sulfuro de Hidrógeno/metabolismo , Canales KATP/agonistas , Canales KATP/metabolismo , Masculino , Simulación del Acoplamiento Molecular , NG-Nitroarginina Metil Éster/antagonistas & inhibidores , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo III/química , Óxido Nítrico Sintasa de Tipo III/metabolismo , Extractos Vegetales/química , Unión Proteica , Ratas , Triterpenos/aislamiento & purificación , Vasodilatadores/aislamiento & purificación , Ácido UrsólicoRESUMEN
BACKGROUND: Prolactin (PRL) reduces joint inflammation, pannus formation, and bone destruction in rats with polyarticular adjuvant-induced arthritis (AIA). Here, we investigate the mechanism of PRL protection against bone loss in AIA and in monoarticular AIA (MAIA). METHODS: Joint inflammation, trabecular bone loss, and osteoclastogenesis were evaluated in rats with AIA treated with PRL (via osmotic minipumps) and in mice with MAIA that were null (Prlr-/-) or not (Prlr+/+) for the PRL receptor. To help define target cells, synovial fibroblasts from Prlr+/+ mice were treated or not with proinflammatory cytokines ((Cyt), including TNFα, IL-1ß, and interferon (IFN)γ) with or without PRL, and these synovial cells were co-cultured or not with bone marrow osteoclast progenitors from Prlr+/+ or Prlr-/- mice. RESULTS: In AIA, PRL treatment reduced joint swelling, increased trabecular bone area, lowered osteoclast density, and reduced mRNA levels of osteoclast-associated genes (tartrate-resistant acid phosphatase (Trap)), cathepsin K (Ctsk), matrix metalloproteinase 9 (Mmp9), and receptor activator of nuclear factor κB or RANK (Tnfrsf11a)), of genes encoding cytokines with osteoclastogenic activity (Tnfa, Il1b, Il6, and receptor activator of nuclear factor κB ligand or RANKL (Tnfrsf11)), and of genes encoding for transcription factors and cytokines related to T helper (Th)17 cells (Rora, Rorc, Il17a, Il21, Il22) and to regulatory T cells (Foxp3, Ebi3, Il12a, Tgfb1, Il10). Prlr-/- mice with MAIA showed enhanced joint swelling, reduced trabecular bone area, increased osteoclast density, and elevated expression of Tnfa, Il1b, Il6, Trap, Tnfrsf11a, Tnfrsf11, Il17a, Il21, Il22, 1 l23, Foxp3, and Il10. The expression of the long PRL receptor form increased in arthritic joints, and in synovial membranes and cultured synovial fibroblasts treated with Cyt. PRL induced the phosphorylation/activation of signal transducer and activator of transcription-3 (STAT3) and inhibited the Cyt-induced expression of Il1b, Il6, and Tnfrsf11 in synovial fibroblast cultures. The STAT3 inhibitor S31-201 blocked inhibition of Tnfrsf11 by PRL. Finally, PRL acted on both synovial fibroblasts and osteoclast precursor cells to downregulate Cyt-induced osteoclast differentiation. CONCLUSION: PRL protects against osteoclastogenesis and bone loss in inflammatory arthritis by inhibiting cytokine-induced expression of RANKL in joints and synovial fibroblasts via its canonical STAT3 signaling pathway.