Hope for arthritis, heart attack, stroke relief found in unique 'acid active' receptor


Reactions similar to synovial cell survival in joint inflammation seen in heart attacks, stroke, gout even muscles. Proton-sensing G-protein coupled receptor operates normally in acidic conditions, indicating potential new therapeutic avenue.

BETHESDA, Md. (Oct. 24, 2005) The fact that arthritis pain and inflammation regularly comes and goes despite drug and other interventions "suggests that additional pathways can rekindle arthritic responses," according to researchers at the University of Texas Medical Branch in Galveston.

Karin Westlund and Terry McNearney, who have been collaborating for almost 10 years, study among other things how the nervous system interacts with peripheral tissues. They note that "a neurogenic contribution to arthritis has long been appreciated with multiple case reports of arthritis sparing or reversing on the patient's paralyzed side after stroke or nerve injury." Working with Burgess Christensen, the lead author of a new paper, and others at UTMB, the team studied the physiology of pain, inflammation and neuroimmune responses in various forms of arthritis, where the pH of joint synovial fluid can be as low as 6, well below normal physiological levels.

Arthritis as a useful model to study cell survival

Westlund said bouts of arthritis such as rheumatoid arthritis or gout are particularly relevant as models to study the actions of an acid-sensing receptor described in the paper because joint tissues are subjected to acidic conditions. "Many normal cellular processes shut down in this acid state, but this new family of receptors we studied operates fully at this low pH," Westlund noted. (A pH of 7 is neutral, below 7 is acidic, above 7 is alkaline and the normal physiologic pH is 7.4).

"The thin synovial lining of a joint capsule is normally made up of only one to four layers of synoviocytes (synovial cells), and its survival is necessary for joint integrity and proper functioning under a variety of conditions," Westlund said, adding: "The discovery that these receptors on human synoviocytes activate calcium during low pH or acidic states supports an important role for their functioning during normal activities as well as in arthritic diseases."

Westlund said that, "Perhaps when the body anticipates a low pH situation, such as an athlete preparing for exercise or an upcoming gouty arthritis attack, these acid-sensing receptors function to protect the cells by temporarily allowing the cell to perform selective functions in an acidic environment," but noted that this is currently only a theory. "The optimum synovial cellular response of the receptor we studied was at pH6.4, where it activated calcium" in a standard physiological measurement, Westlund said.

McNearney added that besides arthritis, similar acidic conditions "are seen in episodes of extreme events such as heart attack and stroke. " An acid-sensing cellular receptor might also have clinical relevance in these diseases as well as other low oxygen conditions and may play a part in the tissue damage that occurs when normal blood flow resumes, in what is called reperfusion injury."

The paper, "A proton-sensing G-protein coupled receptor mobilizes calcium in human synovial cells," appears in the American Journal of Physiology-Cell Physiology, published by the American Physiological Society. Research was performed by Burgess N. Christensen, Mikhail Y. Kochukov, Terry A. McNearney, Giulio Taglialatela and Karin N. Westlund at the University of Texas Medical Branch, Galveston.

Novel pathway could offer new therapeutic opportunities

"This acid-sensing receptor that we describe in the paper is distinctive because its optimal function was at pH6.4, well below the normal biologic range," McNearney said. The results of the team's human and rat arthritis studies suggest a "novel pathway by which the inflammatory response can be manipulated" outside of the usual methods of dealing with pain and/or inflammation, perhaps with a "second-messenger system" just inside the cell. These newly described receptors may also work in tandem with other cellular receptors to enhance selected responses under stressful conditions.

"Ultimately, manipulation of these receptors may enhance cell survival and recovery through activation of protective mechanisms," Westlund said. "Further study of this receptor family may contribute to tissue preservation and improved restoration of tissue function, as well as open new avenues for drug discovery," she added.

Findings hint at receptor role in synovial inflammation, cell proliferation

The new paper describes a "G-protein coupled proton-sensitive receptor that stimulates calcium release from intracellular stores in a tumor-derived synoviocyte cell line and in primary cultures of human synovial cells from patients with inflammatory arthropathies, such as rheumatoid arthritis and psoriatic arthritis." The researchers established a link between proton-dependent receptor activation and intracellular calcium mobilization by demonstrating (1) dependence on the integrity of the intracellular calcium store, (2) independence from extracellular calcium, and (3) proton-induced production of inositol phosphate; and (4) by abolishing the effect by GTP-ase inhibitors."

Based on these findings, the researchers "propose that this G-protein coupled acid-sensing receptor linked to intracellular calcium mobilization in synoviocytes can contribute to downstream inflammatory and cellular proliferative processes in synovial fibroblasts. The acid-sensing receptor has distinct characteristics as a metabotropic G-protein coupled receptor on human synoviocytes in this emerging new class of receptors."

Next steps

The paper noted several findings, among many others, that require further research:

  • It is necessary to further study whether the observed calcium mobilization in lower pH is somehow "involved in important signaling pathways during the development of arthritis and other systemic, ischemic and inflammatory processes."

  • "An important question is whether these acid-evoked responses are important in fibroblast-derived cells under normal physiological conditions, or more particularly, in ischemic and inflammatory conditions where destructive and reperfusion processes regularly occur, for example, in synovial and muscle tissues."

  • Westlund added: "This class of receptors seems pretty ubiquitous. We don't yet understand their function, but the fact that they're in places where they must respond to differing pH situations might indicate different receptor-activation potential in different tissues."

Source and funding

The paper "A proton-sensing G-protein coupled receptor mobilizes calcium in human synovial cells" appears in the American Journal of Physiology-Cell Physiology, published by the American Physiological Society. Research was performed by Burgess N. Christensen, Mikhail Y. Kochukov, Terry A. McNearney, Giulio Taglialatela and Karin N. Westlund, at the University of Texas Medical Branch, Galveston, Dept. of Neuroscience and Cell Biology; McNearney is also at the Dept. of Internal Medicine, and the Dept. of Microbiology and Immunology.

Research was funded by the Dana Foundation and National Institutes of Health.

Editor's note: The media may obtain a copy of Christensen, Westlund et al. by contacting Mayer Resnick, American Physiological Society, 301-634-7209, cell 301-332-4402 or [email protected].

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