Hyperuricemia and Lubricin in Gout Treatment
In this video, Robert Terkeltaub, MD, discusses his team's latest research on the pathophysiology of gout in patients with and without hyperuricemia, as well as a potential pathway for treatment by way of a molecule called lubricin.
- Elsaid K, Merriman TR, Rossitto LA, et al. Amplification of inflammation by lubricin deficiency implicated in incident, erosive gout independent of hyperuricemia. Arthritis Rheumatol. Published online December 1, 2022. Accessed March 14, 2023. https://doi.org/10.1002/art.42413
- New look at an ancient disease: study finds novel treatment targets for gout. News release. University of California San Diego; December 13, 2022. Accessed March 14, 2023. https://today.ucsd.edu/story/new-look-at-an-ancient-disease-study-finds-novel-treatment-targets-for-gout
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Robert Terkeltaub, MD, is a professor of medicine emeritus in the Division of Rheumatology, Allergy and Immunology at the University of California, San Diego.
Hi, I'm Bob Terkeltaub and I'm a Professor of Medicine Emeritus at UC San Diego and I'm a rheumatologist.
We've neglected to think about a couple of factors that are probably very important in gout. The average patient that comes to see us, in 99% plus of cases have a background of hyperuricemia for years, a very significant hyperuricemia background. Maybe their hyperuricemia is better now because one or two of the risk factors are better. Maybe they've lost a lot of weight, maybe they're drinking less alcohol, maybe their kidney function improved, et cetera. But, 99% plus of the people that come to us have hyperuricemia or significant background hyperuricemia. That said, have we thought enough about who gets gout?
About 21% or so of the USA population have hyperuricemia, but only about 5% of the adult US population, has gout. So, not everybody with hyperuricemia gets gout, no matter what the serum urate is. Yes, the higher the serum urate, the higher the risk. And there is the concept that what's happening is that the high serum urate percolates into the joint and that’s the only reason why urate crystals deposits in the joint tissues. And you develop gout because of the tissue inflammatory reaction to those crystals. Well, that needs to be challenged based on a number of things, including my own recent research, which is now available open access online.
The research was prompted by a very unusual case of a 22 year old female who never had a high serum urate, hadno family history of gout, and despite a normal serum urate of 5 milligrams per deciliter, developed very aggressive and erosive gouty arthritis with crystal deposits. Classic erosions of gout, which indicate tophaceous disease in the joint. And then when her serum urate was lowered to 2 mg/dL by allopurinol, she got better. Although she got Crohn's disease later. There was clearly some sort of abnormality in this patient, and probably a complex one because we don't see 22 year old females get gout without an obvious reason. In fact, it's very unusual to see premenopausal females get gout, but unheard of in somebody with normal serum urate. Just as with other diseases, for example HIV, there are situations when you discover a very important pathophysiology of a disease because somebody’s HIV burden clears. For example, with HIV, if they got a stem cell transplant for acute leukemia. Things like that happen.
We were able to characterize the 22 year old female normouricemic gout patient in detail using whole genome sequencing and other analytics. Using screening proteomics and then looking at the biology of this, in model systems including small animal modeling, and cell culture modeling systems we tried to understand and answer a number of questions. First, why do only a minority of people with longstanding high serum urate get gout? And second, what determines that a gout patient progresses to tophaceous and erosive disease? We can look foir something that we can identify which is new and responsible for the unusual case. And perhaps, some things in the joints themselves that determine whether people will get gout, whether it will progress, or both.
So that's what we did. We started with whole genome sequencing. That generally doesn't provide all the answers. But there were some quite interesting findings. There was a propensity in this patient to have more inflammatory disease based on multiple variants of a gene called NLRP3, which leads to production of the cytokine IL-1β, the “boss cytokine” in gouty inflammation. And then there were other genetic variants of interest. particularly inhibitors of proteases that break down components of our normal matrix, including matrix constituents that lubricate the surfaces of the cartilage and joint lining. And lubricin is one of the substrates of some of these proteases. And other gene variants that mediate how inflammation resolves.
There was a lot of genetic baggage that this unfortunate young patient carried in into this. We next did proteomics of serum. With the way the proteomics is done now, you can detect thousands of proteins in serum. We looked at things that were decreased by tenfold or more in the patient's serum compared to the parents, neither of whom had gout. And compared to healthy people, we looked for things that are more than tenfold increased. And then we tried to find candidate molecules that would make sense. In particular, we looked for deficiency states more than disease due to protein excess.
Screening proteomics found a tremendous drop in the joint lubricant called lubricin, which is a very large and slippery molecule that sits on surfaces and allows the long bones to glide on each other because the cartilage is lubricated. And there's another molecule called superficial-zone protein which is very similar to lubricin but it's not secreted in great amounts into the blood so it's harder to detect. But these are closely related lubricants.
We found that the unfortunate patient, with aggressive, destructive gout without hyperuricemia, had a marked decrease in serum lubricin. We looked at gout patients and there were a fair number of patients who had also very, very low lubricin levels. Not everybody, but about a quarter of the gout patients that we analyzed. And we looked at the enzymes that break down lubricin and their regulators, using serum proteomics and genomics in particular. We found genetic change in a couple of the molecules that control the enzymes that break down lubricin.
We also found in the serum that there was an increase in lubricin degrading enzyme activity. One of the proteases that degrade lubricin is cathepsin G, and its activity and one of the activators of cathepsin G were in excess, not only in the patient but collectively in gout patients. There was a lot higher Cathepsin G activity in the blood in the patient. So we went deeper. Lubricin is present at a pretty robust concentration in the joint. So, we looked at the concentrations in the joint fluid of lubricin and prepared a solution with a high uric acid content, high soluble urate content, and looked for crystallization of the urate.
And we found that at the concentrations lubricin is normally at in joint fluid, it markedly suppressed the ability of the urate crystals to form. We were quite excited about that result. Then we looked at the possibility that lubricin does more, since lubricin interacts with a number of cells. One of the cell is the macrophage, and it lives in the synovium. Also monocytes come in from the bone marrow and blood and they turn into macrophages in the joint. Those macrophages promote inflammation. What we studied was whether lubricin inhibited the ability of those macrophages to actually produce uric acid in the joint. And that’s important because people have focused solely on the idea that it's the high serum urate percolating passively into the joint that is responsible for whether people get gout or not.
Lubricin profoundly inhibited the ability of macrophages stimulated by IL-1β to actually express the enzyme that makes uric acid: xanthine oxidase. The enzyme we inhibit with allopurinol and with febuxostat. Also, the ability of these cells to produce uric acid was blunted by lubricin. So we implicated a regulatory circuit where if you have high activity of inflammatory cells (phagocytes) and you have high levels of active proteases that are breaking down lubricin, you will get more local uric acid production in the joint by xanthine oxidase in cells that reside in the joint. Basically, the patient with unusual gout had a perfect storm of elements to develop gout without hyperuricemia. There was more NLRP3 activation to stimulate more IL-1β to drive uric acid production in the joint, and had more, uninhibited protease activity to break down lubricin.
There was no actual defect in terms of the expression of the gene of the lubricin, of the PRG4 gene. It was a protein breakdown issue in the patient. The model is that you have local xanthine oxidase and that is normally regulated by lubricin, and loss of that regulation is a major factor in gout progressing to erosive disease and also just getting gout because of crystallization of urate and the resulting inflammatory consequences. The idea that lubricin is part of the package and a major natural suppressor of getting gout is truly novel.
Lubricin is a very large molecule, slippery, and difficult to make. And that's impeded study of lubricin and and also slowed the development of lubricin as a therapeutic. Measures to stabilize the lubricin that's naturally there in the joint could be of great value for gout. Also, inhibiting some of these proteases that break down lubricin is likely to be of value. And, the fact is that we use systemic xanthine oxidase inhibition therapy in our treat to target strategy, with the first line therapy as allopurinol, and the second line as febuxostat. The fact is that these are truly disease modifying therapeutics for gout, and they promote ultimate improvement of the symptom burden. So, our first line drugs being xanthine oxidase inhibitors makes inherent sense. And, for the bottom line, a joint lubricant also limits gout, which is novel and exciting.