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Arthritis & Rheumatism

Researchers identify new arthritis severity gene

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A new gene associated with disease severity in models of rheumatoid arthritis has been identified by researchers at the Icahn School of Medicine at Mount Sinai. The discovery could provide a new pathway for treatment and a way to measure the prognosis of patients diagnosed with the autoimmune condition.

Through a series of experiments—on synovial cells from the inner lining of joints in humans and animals, and in animal models of arthritis—Percio S. Gulko, MD, Chief of the Division of Rheumatology, Lillian and Henry M. Stratton Professor of Medicine (Rheumatology), and senior author on the paper, and his colleagues were able to show that the gene HIP1 is a driver in inflammatory arthritis severity. This is the first time that HIP1 has been implicated in arthritis severity and in cell invasiveness. The findings will be published online in Annals of the Rheumatic Diseases on Thursday, July 26.

Rheumatoid arthritis is a chronic disease affecting more than 1.3 million Americans. The disease can cause disability and deformation of joints and affects roughly 1 percent of the world’s population. Drugs currently available to treat rheumatoid arthritis target the body’s immune response but raise the risk of immunosuppression and susceptibility to infections such as herpes zoster and pneumonia.

“There have been major advances in the treatment of rheumatoid arthritis in the past 20 years, but disease remission still remains uncommon. Most drugs today target inflammation but often that is not enough to control disease,” says Dr. Gulko. “At my laboratory, we have been looking for alternative strategies. In this research, we have focused on understanding the regulation of disease severity and joint damage. Our discovery led us to the synovial fibroblasts, cells inside the joint.”

Through genetic strategies including linkage mapping and congenic breeding, in which specific chromosome fragments in arthritis-susceptible rodent strains are replaced with chromosome fragments from arthritis-resistant strains, Dr. Gulko and his co-researchers identified a chromosomal region that controls arthritis severity and joint damage.

This region contained 41 genes. They sequenced those genes and discovered a mutation in HIP1, a gene previously unrelated to arthritis or inflammation. The lab was then able to show that the different forms (alleles) of HIP1 affected the behavior of the synovial fibroblast, the cells that line the tissue in the inner surface of joints, by reducing or augmenting invasiveness of the cells. Synovial fibroblast enables local repair and production of the fluid that lubricates joints and nourishes the joint cartilage. In people with rheumatoid arthritis, the synovial fibroblasts increase in numbers (hyperplasia) and become invasive, and the synovial tissue becomes infiltrated with immune cells, causing joint swelling and pain. This invasive behavior is known to correlate with joint damage in patients with rheumatoid arthritis.

With this crucial information, the researchers moved on to the next experiment in synovial fibroblasts derived from patients with rheumatoid arthritis. The researchers knocked down (removed) the HIP1 gene in these synovial fibroblasts. Removing HIP1 significantly reduced the ability of the rheumatoid arthritis synovial fibroblasts to respond to PDGF (platelet-derived growth factor), a potent inducer of synovial fibroblast invasiveness expressed in increased levels in the joints of patients with rheumatoid arthritis. Knockdown of HIP1 prevented the activation of the signaling molecule Rac1, which is key for synovial fibroblast invasiveness. Dr. Gulko and his colleagues also studied HIP1-deficient mice. These mice were protected, and developed a milder form of the arthritis.

Previous research had found that increased HIP1 expression in certain cancers and correlated with worse prognosis in prostate cancer patients. Therefore, Dr. Gulko’s findings also have potential relevance for cancer biology and the understanding of cancer cell invasion and metastasis.

“These new discoveries raise the future possibility of targeting HIP1 to treat rheumatoid arthritis, and also of quantifying HIP1 levels in the blood or synovial fluid cells to predict disease outcome,” said Dr. Gulko.

Dr. Gulko’s research provides a framework for a potential new target for therapy and, perhaps, a new predictor of a patient’s prognosis. He and his colleagues plan in the future to investigate the feasibility of a drug that would target the HIP1 gene. “We are aiming for a novel way of treating the disease. One that targets the synovial fibroblast, while sparing the immune system outside the joint,” he says.

Source: The Mount Sinai Hospital

Arthritis & Rheumatism

Dietary carbohydrates could lead to osteoarthritis, new study finds

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Do your knees ache? According to new findings from the Oklahoma Medical Research Foundation, your diet could be a culprit.

In a study led by OMRF scientist Tim Griffin, Ph.D., researchers found that the carbohydrate composition of diets increased the risk of osteoarthritis in laboratory mice—even when the animals didn’t differ in weight.

“We know increased body fat elevates risk, but we haven’t appreciated as much how diet itself affects the disease risk,” said Griffin. “These findings give us new clues that there can be significant dietary effects linked to increased OA risk even in the absence of obesity.”

Osteoarthritis, or OA, is the most common form of arthritis and the most widespread form of disability in the country, affecting nearly 27 million people in the U.S. It occurs when the cartilage that cushions bones in the joints breaks down and wears away, causing the bones to rub against one another.

Several factors can increase risk, including high-impact physical jobs, previous joint injuries, age and genetics, but carrying extra body weight is among the most proven contributors.

“Obesity is the one of the most significant factors for developing disease in the knee joint,” said Griffin. “However, therapeutic strategies to prevent or treat obesity-associated OA are limited because of the uncertainly about the root cause of the disease.”

To study how, exactly, obesity contributes to osteoarthritis, Griffin and his lab placed groups of mice on different high-fat diets. However, over time, they observed that the carbohydrate makeup of the rodents’ low-fat control diet was alone sufficient to alter their chances of developing OA.

The primary culprits: fiber and sugar.

In particular, Griffin’s team found that changing the amount of sucrose—table sugar—and fiber in the diet altered OA pathology in the rodents. The high-sucrose diet increased signs of joint inflammation, while the high-fiber diet caused changes in cartilage genes and cellular stress-response pathways.

While the study involved mice, Griffin said the findings could ultimately have human implications.

“It’s important to understand how our diet affects the health of our joints,” he said. “We were surprised to see so many OA-related differences between the two high-carb diets even though body weight and body fat were the same.”

Griffin next plans to investigate how different types of dietary fiber and other components of our diets can contribute to OA, and also look at the role the body’s microbiome and gut bacteria play in the disease.

 

More information: Elise L. Donovan et al, Independent effects of dietary fat and sucrose content on chondrocyte metabolism and osteoarthritis pathology in mice, Disease Models & Mechanisms (2018).DOI: 10.1242/dmm.034827

Provided by: Oklahoma Medical Research Foundation

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Arthritis & Rheumatism

Dietary carbohydrates could lead to osteoarthritis, new study finds

Published

on

Do your knees ache? According to new findings from the Oklahoma Medical Research Foundation, your diet could be a culprit.

In a study led by OMRF scientist Tim Griffin, Ph.D., researchers found that the carbohydrate composition of diets increased the risk of osteoarthritis in laboratory mice—even when the animals didn’t differ in weight.

“We know increased body fat elevates risk, but we haven’t appreciated as much how diet itself affects the disease risk,” said Griffin. “These findings give us new clues that there can be significant dietary effects linked to increased OA risk even in the absence of obesity.”

Osteoarthritis, or OA, is the most common form of arthritis and the most widespread form of disability in the country, affecting nearly 27 million people in the U.S. It occurs when the cartilage that cushions bones in the joints breaks down and wears away, causing the bones to rub against one another.

Several factors can increase risk, including high-impact physical jobs, previous joint injuries, age and genetics, but carrying extra body weight is among the most proven contributors.

“Obesity is the one of the most significant factors for developing disease in the knee joint,” said Griffin. “However, therapeutic strategies to prevent or treat obesity-associated OA are limited because of the uncertainly about the root cause of the disease.”

To study how, exactly, obesity contributes to osteoarthritis, Griffin and his lab placed groups of mice on different high-fat diets. However, over time, they observed that the carbohydrate makeup of the rodents’ low-fat control diet was alone sufficient to alter their chances of developing OA.

The primary culprits: fiber and sugar.

In particular, Griffin’s team found that changing the amount of sucrose—table sugar—and fiber in the diet altered OA pathology in the rodents. The high-sucrose diet increased signs of joint inflammation, while the high-fiber diet caused changes in cartilage genes and cellular stress-response pathways.

While the study involved mice, Griffin said the findings could ultimately have human implications.

“It’s important to understand how our diet affects the health of our joints,” he said. “We were surprised to see so many OA-related differences between the two high-carb diets even though body weight and body fat were the same.”

Griffin next plans to investigate how different types of dietary fiber and other components of our diets can contribute to OA, and also look at the role the body’s microbiome and gut bacteria play in the disease.

More information: Elise L. Donovan et al, Independent effects of dietary fat and sucrose content on chondrocyte metabolism and osteoarthritis pathology in mice, Disease Models & Mechanisms (2018).DOI: 10.1242/dmm.034827

Provided by: Oklahoma Medical Research Foundation

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Arthritis & Rheumatism

Emotions like anger and sadness may cause pain as well as being a result of it

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While emotions such as anger or sadness are often thought of as being a result of stress or pain, findings recently published by Penn State researchers suggest that negative or mixed emotions could function as stressors themselves.

The manuscript, published in the journal Psychological Reports on Sept. 6, examines the relationship between emotion and pain among women with rheumatoid arthritis (RA).

“We often think of emotion as a consequence of stress or pain, but our findings suggest that under certain circumstances negative emotion or complex, mixed emotion can function as a stressor itself, and one which can promote inflammation,” said Jennifer Graham-Engeland, associate professor of biobehavioral health and lead author of the manuscript.

Graham-Engeland and her colleagues hypothesized that inflammation – a physiological phenomenon for which biomarkers from blood can be obtained – may be connected to emotion and pain. They developed a novel methodology and used it to test how emotional state, such as anger, sadness or happiness, affected inflammatory response to a pain stimulus.

“The more we understand the connection between emotion and pain the more we can develop newer options for treatment as well as bolster the argument that psychological treatments are needed for pain,” Graham-Engeland said.

Study participants each came for a five-hour visit on four separate occasions to the Clinical Research Center at Penn State. These visits varied only by the manipulation of emotion (anger, sadness or happiness versus a non-emotional control visit). To manipulate emotion, researchers had participants think, write and talk about their recent feelings related to one of these specific emotions.

After the emotion manipulation, acute pain was caused by pressing on tender or swollen joints of participants, such as what might be done during a routine clinical exam. Blood samples were then obtained at multiple time points, including at baseline, ten minutes, one hour, and 100 minutes after the pain stimulus.

There was no main effect of experimental condition; however, when participants reported greater anger than their own average, they showed elevated inflammation, Graham-Engeland said.

“These findings are in concordance with a few recent studies suggesting that emotional states can cause or contribute to specific patterns of physiological responses to stress or pain,” said Graham-Engeland.

Researchers also found that when negative emotion was experienced in the context of a manipulation for a different emotion—for example, if participants felt sadness when researchers were trying to get them to focus on angry feelings—they showed elevated levels of both inflammation and the stress hormone cortisol.

Such work is important because a more nuanced understanding of the role of emotion, psychological stress and pain on inflammatory states may eventually help clarify novel clinical tools to treat inflammation and pain or help improve current pain management techniques, Graham-Engeland said.

Though these findings relate specifically to patients with RA, Graham-Engeland said in the future this work can potentially inform other pain patients.

“I’m optimistic this may turn out to be relevant more broadly,” she said. “Additional research is needed to advance the findings of this preliminary research, both among the clinical and healthy populations.”

More information: Jennifer E. Graham-Engeland et al. Emotional State Can Affect Inflammatory Responses to Pain Among Rheumatoid Arthritis Patients: Preliminary Findings, Psychological Reports (2018). DOI: 10.1177/0033294118796655

Provided by: Pennsylvania State University

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