New Target for Treatment of Gout / Nuovo obiettivo per il trattamento della gotta
New Target for Treatment of Gout / Nuovo obiettivo per il trattamento della gotta
Segnalato dal Dott. Giuseppe Cotellessa / Reported by Dr. Giuseppe Cotellessa
Researchers at Washington State University Health Sciences Spokane and elsewhere have identified a new therapeutic target for the treatment of gout, a common type of arthritis that causes episodes of painful and stiff joints.
Published in the journal Cellular and Molecular Immunology, their study suggests that blocking a signaling molecule known as TAK1 can suppress inflammation caused by gout. The research lays the foundation for the development of potential new treatment strategies that could significantly improve the quality of life of millions of people around the world who suffer from the condition. In the United States alone, gout affects an estimated 8.3 million people, or about 4 percent of the population.
Gout is caused by high blood levels of uric acid, a natural waste product from the digestion of foods that contain purines, such as red meat, seafood, dried beans, and beer. Elevated uric acid levels can lead to the formation of monosodium uric acid (MSU) crystals that accumulate in joints. The immune system will perceive these crystals as a threat and launch an immune response against them that increases the production of interleukin-1-beta (IL-1-beta), a cytokine protein that causes inflammation and triggers the intense pain and swelling people experience during gout attacks.
“It’s kind of a vicious cycle that starts with these crystals, which cause IL-1-beta to be produced, inducing inflammation and activating a lot of other proteins to produce more inflammation,” said Salah-Uddin Ahmed, a professor of pharmaceutical sciences in the WSU College of Pharmacy and Pharmaceutical Sciences and senior author on the study.
One of those proteins activated by IL-1-beta—TAK1—caught the interest of Ahmed’s research team when their previous study suggested its key role in the regulation of IL-1-beta inflammation in rheumatoid arthritis. They designed a study to identify the molecular mechanism by which MSU crystals produce IL-1-beta inflammation and the role of TAK1 in this process. Using two different cell lines of human macrophages—immune cells that play a key role in inflammation—they found that MSU crystals could directly activate TAK1 and other proteins that were previously thought to be dependent on IL-1-beta signaling for activation.
“We already knew that MSU crystals activate what is known as the inflammasome pathway, which produces IL-1-beta,” Ahmed said. “However, our study found that MSU crystals also use an alternate pathway that triggers inflammation through TAK1, which is a new finding related to how gout develops.”
Next, they showed that the use of a chemical that inhibits, or blocks, TAK1 could completely suppress any inflammation caused by MSU crystals, both in healthy human macrophage cells and in a rodent model of gout.
Ahmed said their discovery has opened the door towards the development of new treatment strategies for gout.
One current treatment he said scientists have experimented with is Anakinra, a drug that blocks the binding of IL-1-beta to its receptor. Though it has shown promise, Ahmed said the drug is not clinically used for gout, because it is given by infusion—which requires hospitalization; its effectiveness is limited; and it comes with a potential risk of infections when used long term. Developing TAK1 inhibitor drugs that could be taken by mouth would allow patients with gout to manage flare-ups of the disease at home.
The team’s next goal is to confirm their findings in cells taken from patients with gout. They are currently pursuing federal funding for this project, which they plan to conduct in collaboration with clinical scientists at the University of Alabama Birmingham and the University of Michigan Ann Arbor. If their findings hold up, this may eventually lead to clinical trials to test TAK1-inhibitors in patients.
Ahmed said their finding could also eventually be tested in other diseases that involve IL-1-beta mediated inflammation, such as multiple sclerosis, inflammatory bowel disease, and type 1 diabetes.
Published in the journal Cellular and Molecular Immunology, their study suggests that blocking a signaling molecule known as TAK1 can suppress inflammation caused by gout. The research lays the foundation for the development of potential new treatment strategies that could significantly improve the quality of life of millions of people around the world who suffer from the condition. In the United States alone, gout affects an estimated 8.3 million people, or about 4 percent of the population.
Gout is caused by high blood levels of uric acid, a natural waste product from the digestion of foods that contain purines, such as red meat, seafood, dried beans, and beer. Elevated uric acid levels can lead to the formation of monosodium uric acid (MSU) crystals that accumulate in joints. The immune system will perceive these crystals as a threat and launch an immune response against them that increases the production of interleukin-1-beta (IL-1-beta), a cytokine protein that causes inflammation and triggers the intense pain and swelling people experience during gout attacks.
“It’s kind of a vicious cycle that starts with these crystals, which cause IL-1-beta to be produced, inducing inflammation and activating a lot of other proteins to produce more inflammation,” said Salah-Uddin Ahmed, a professor of pharmaceutical sciences in the WSU College of Pharmacy and Pharmaceutical Sciences and senior author on the study.
One of those proteins activated by IL-1-beta—TAK1—caught the interest of Ahmed’s research team when their previous study suggested its key role in the regulation of IL-1-beta inflammation in rheumatoid arthritis. They designed a study to identify the molecular mechanism by which MSU crystals produce IL-1-beta inflammation and the role of TAK1 in this process. Using two different cell lines of human macrophages—immune cells that play a key role in inflammation—they found that MSU crystals could directly activate TAK1 and other proteins that were previously thought to be dependent on IL-1-beta signaling for activation.
“We already knew that MSU crystals activate what is known as the inflammasome pathway, which produces IL-1-beta,” Ahmed said. “However, our study found that MSU crystals also use an alternate pathway that triggers inflammation through TAK1, which is a new finding related to how gout develops.”
Next, they showed that the use of a chemical that inhibits, or blocks, TAK1 could completely suppress any inflammation caused by MSU crystals, both in healthy human macrophage cells and in a rodent model of gout.
Ahmed said their discovery has opened the door towards the development of new treatment strategies for gout.
One current treatment he said scientists have experimented with is Anakinra, a drug that blocks the binding of IL-1-beta to its receptor. Though it has shown promise, Ahmed said the drug is not clinically used for gout, because it is given by infusion—which requires hospitalization; its effectiveness is limited; and it comes with a potential risk of infections when used long term. Developing TAK1 inhibitor drugs that could be taken by mouth would allow patients with gout to manage flare-ups of the disease at home.
The team’s next goal is to confirm their findings in cells taken from patients with gout. They are currently pursuing federal funding for this project, which they plan to conduct in collaboration with clinical scientists at the University of Alabama Birmingham and the University of Michigan Ann Arbor. If their findings hold up, this may eventually lead to clinical trials to test TAK1-inhibitors in patients.
Ahmed said their finding could also eventually be tested in other diseases that involve IL-1-beta mediated inflammation, such as multiple sclerosis, inflammatory bowel disease, and type 1 diabetes.
ITALIANO
I ricercatori della Washington State University Health Sciences Spokane e altrove hanno identificato un nuovo obiettivo terapeutico per il trattamento della gotta, un tipo comune di artrite che provoca episodi di articolazioni dolorose e rigide.
Pubblicati sulla rivista Cellular and Molecular Immunology, il loro studio suggerisce che il blocco di una molecola di segnalazione nota come TAK1 può sopprimere l'infiammazione causata dalla gotta. La ricerca pone le basi per lo sviluppo di potenziali nuove strategie di trattamento che potrebbero migliorare significativamente la qualità della vita di milioni di persone in tutto il mondo che soffrono di questa condizione. Solo negli Stati Uniti, la gotta colpisce circa 8,3 milioni di persone, pari a circa il 4% della popolazione.
La gotta è causata da alti livelli ematici di acido urico, un prodotto di scarto naturale dalla digestione di cibi che contengono purine, come carne rossa, frutti di mare, fagioli secchi e birra. Livelli elevati di acido urico possono portare alla formazione di cristalli di acido urico monosodico (MSU) che si accumulano nelle articolazioni. Il sistema immunitario percepirà questi cristalli come una minaccia e lancerà una risposta immunitaria contro di essi che aumenta la produzione di interleuchina-1-beta (IL-1-beta), una proteina citochina che provoca infiammazione e innesca il dolore intenso e il gonfiore che le persone sperimentano durante gli attacchi di gotta.
"È una specie di circolo vizioso che inizia con questi cristalli, che causano la produzione di IL-1-beta, inducendo l'infiammazione e attivando molte altre proteine per produrre più infiammazione", ha affermato Salah-Uddin Ahmed, professore di scienze farmaceutiche nel WSU College of Pharmacy and Pharmaceutical Sciences e autore senior dello studio.
Una di quelle proteine attivate dall'IL-1-beta — TAK1 — ha catturato l'interesse del gruppo di ricerca di Ahmed quando il loro precedente studio ha suggerito il suo ruolo chiave nella regolazione dell'infiammazione dell'IL-1-beta nell'artrite reumatoide. Hanno progettato uno studio per identificare il meccanismo molecolare attraverso il quale i cristalli di MSU producono infiammazione dell'IL-1-beta e il ruolo di TAK1 in questo processo. Utilizzando due diverse linee cellulari di macrofagi umani - cellule immunitarie che svolgono un ruolo chiave nell'infiammazione - hanno scoperto che i cristalli MSU potevano attivare direttamente TAK1 e altre proteine che in precedenza si pensava dipendessero dalla segnalazione di IL-1-beta per l'attivazione.
"Sapevamo già che i cristalli MSU attivano quello che è noto come il percorso dell'inflammasoma, che produce IL-1-beta", ha detto Ahmed. "Tuttavia, il nostro studio ha scoperto che i cristalli di MSU usano anche un percorso alternativo che innesca l'infiammazione attraverso TAK1, che è una nuova scoperta relativa allo sviluppo della gotta."
Successivamente, hanno dimostrato che l'uso di una sostanza chimica che inibisce, o blocca, TAK1 potrebbe sopprimere completamente qualsiasi infiammazione causata dai cristalli di MSU, sia in cellule di macrofagi umani sani che in un modello di gotta di roditori.
Ahmed ha affermato che la loro scoperta ha aperto le porte allo sviluppo di nuove strategie terapeutiche per la gotta.
Un trattamento attuale che ha detto che gli scienziati hanno sperimentato è Anakinra, un farmaco che blocca il legame di IL-1-beta al suo recettore. Sebbene abbia mostrato risultati promettenti, Ahmed ha affermato che il farmaco non è clinicamente usato per la gotta, perché è somministrato per infusione, che richiede il ricovero in ospedale; la sua efficacia è limitata; e comporta un potenziale rischio di infezione se usato a lungo termine. Lo sviluppo di farmaci inibitori TAK1 che potrebbero essere assunti per via orale consentirebbe ai pazienti con gotta di gestire le riacutizzazioni della malattia a casa.
Il prossimo obiettivo del gruppo è confermare i loro risultati nelle cellule prelevate da pazienti con gotta. Attualmente stanno perseguendo finanziamenti federali per questo progetto, che intendono condurre in collaborazione con scienziati clinici dell'Università di Alabama Birmingham e dell'Università del Michigan Ann Arbor. Se le loro scoperte reggono, ciò può eventualmente condurre a studi clinici per testare inibitori di TAK1 nei pazienti.
Ahmed ha affermato che la loro scoperta potrebbe anche essere testata in altre malattie che coinvolgono infiammazione mediata da IL-1-beta, come la sclerosi multipla, la malattia infiammatoria intestinale e il diabete di tipo 1.
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