BERKELEY, CA (UroToday.com) - Daniel Culkin, MD, Chair of Urology and lead clinical researcher teamed with Robert Hurst, PhD to investigate changes in the bladder urothelium that lead to the loss of impermeability. For an earlier paper¹ a set of shallow cold-cup biopsies was collected under very rigidly controlled conditions from patients who all experienced moderate to severe symptoms. The paper demonstrated multiple abnormalities in E-cadherin, ZO-1, and uroplakin, the glycosaminoglycan chondroitin sulfate and the morphology and cellular polarity of the urothelium. The current study aimed at digging deeper into the expression of molecules involved with differentiation and the so-called GAG layer and therefore analyzed expression of proteoglycan core proteins to determine the cause of the loss of chondroitin sulfate seen in IC-derived biopsies and cytokeratins to further define the change in the differentiation program. The current data were analyzed together with the earlier data using clustering algorithms to identify natural groupings among the data.

Our initial clustering analysis as originally submitted showed that the markers fell naturally into three major groups: all the proteoglycan core proteins and the tight junction protein, ZO-1; differentiation-related markers including the cytokeratins, uroplakin, and the morphology-polarity score, and a single protein, E-cadherin, which was overexpressed in IC. Susan Keay, MD, reported earlier that the mRNA of E-cadherin also was overexpressed in the urothelium of IC patients². The samples themselves fell naturally into 4 groups. All the normals clustered together and were distinct from the patient samples. One group consisted of biopsies in which most of the findings were abnormal. A second group was similar, but not quite so severe. A third group consisted of samples in which the predominant finding was abnormal E-cadherin with most of the other markers showing a normal or near normal distribution. Due to the suggestion of a perceptive reviewer, we added an assessment of inflammation in the specimens by Barbara Bane, MD, our uropathologist. This led to the important finding that inflammation correlated very poorly with any of the other markers, indicating that inflammation could not be the cause of the altered differentiation seen in the urothelium of IC patients. This paper shows both qualitative and quantitative changes in the expression of GAG layer and tight junction proteins (“defenses molecules”) and differentiation proteins can be defined in IC and perhaps used both to understand the pathophysiology of the IC in relation to the wider problem of chronic pelvic pain.

References

1. Slobodov G, Feloney M, Gran C, Kyker KD, Hurst RE, and Culkin DJ . Abnormal Expression of Molecular Markers for Bladder Impermeability and Differentiation in Urothelium of Interstitial Cystitis Patients. J Urol 2004;171:1554-1558.
2. Keay S, Seillier-Moiseiwitsch F, Zhang CO, Chai T, and Zhang J . Changes in human bladder epithelial cell gene expression associated with interstitial cystitis or antiproliferative factor treatment. Physiol Genomics 2003;14:107-115.

Written by
Robert E. Hurst, PhD, as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Abnormal Expression of Differentiation Related Proteins and Proteoglycan Core Proteins in the Urothelium of Patients With Interstitial Cystitis - Abstract

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