Bladder Defense Molecules, Urothelial Differentiation, Urinary Biomarkers, and Interstitial Cystitis

doi:10.1016/j.urology.2006.03.083

Urology

Volume 69, Issue 4, Supplement, April 2007, Pages S17-S23

https://doi.org/10.1016/j.urology.2006.03.083 Get rights and content

It has long been recognized that interstitial cystitis (IC) is a disease of the urothelium. In this article, we review the results of published studies and present new data concerning the precise role of the bladder epithelium in IC. We discuss bladder defenses against both the penetration of urinary solutes and bacterial adherence, and we present new information about the proteoglycans that are present on the normal bladder. Previously published results and new data presented here support the conclusion that IC involves an aberrant differentiation program in the bladder urothelium that leads to altered synthesis of several proteoglycans, cell adhesion and tight junction proteins, and bacterial defense molecules such as GP51. These findings lend support to the rationale for glycosaminoglycan replacement therapy for the treatment of patients with IC.

Section snippets

Urothelium in interstitial cystitis

It is increasingly recognized that distinctive changes at molecular and structural levels occur in the bladder and urothelium as a result or a cause of IC. In general, the bladder exhibits thinning and denudation of urothelium, and distinctive changes are seen in the muscle; involvement that is both perivascular and perineural suggests neurogenic inflammation.⁴ Some pathologic changes in the bladder may result from upregulation of nerve growth factor, leading to increased innervation and pain

Biomarkers for interstitial cystitis

With increasing knowledge of the molecular pathophysiology of IC comes an improved ability to identify biomarkers for the disease. Keay et al.³⁰ recently reviewed the status of several biomarkers that have been proposed as useful in the diagnosis of IC. Most biomarkers probably reflect the effects of the underlying disease process and may be only peripherally related to central pathophysiologic mechanisms and pathways. However, the number of differentiation-associated molecules that are also

Structure and function of proteoglycans and glycosaminoglycans

Proteoglycans are major players in signaling between the stroma and the epithelium and therefore could be important players in the epithelial dysfunction seen in the urothelium of patients with IC. Following is a brief review of the structures of these molecules and how they compare with other carbohydrate-containing proteins. Proteoglycans are complex macromolecules that consist of a central protein, the “core protein,” and ≥ 1 GAG chain covalently attached to the protein through a serine

Identification of proteoglycans expressed in normal bladder

Because little is known about the composition of proteoglycans on normal bladder, we investigated for this review the proteoglycan composition of normal human bladder urothelium using specific antibodies against the core proteins. As is demonstrated later, an unusual suite of proteoglycans was discerned on the bladder luminal surface, and a more typical suite was seen in the extracellular matrix and the lamina propria.

Materials and methods

Tissue sections were obtained from random patient biopsy specimens taken to assess recurrent bladder cancer. Only sections for which all biopsy results were read as histopathologically normal and not associated with a later recurrence were included. Tissue blocks were cut into 5-μm sections, deparaffinized, rehydrated, and incubated with 0.7% H₂O₂ to block endogenous peroxidases. Sections were blocked with 10% normal goat serum for 1 hour and were then incubated with the primary antibody,

Results

The luminal surface showed the presence of decorin and perlecan, but not of versican. Syndecan-1 outlined the surfaces of all cells in the intermediate and basal layers of the normal urothelium but was not found to be a component of the GAG layer. As expected, the deeper connective tissues are rich in these substances, which provided an internal control for staining. Versican is abundant in the vascular tissue, as expected, where it is synthesized by vascular smooth muscle cells.⁴¹

We also

Discussion

Proteoglycans play a number of fundamental and important roles in the extracellular matrix and on cell surfaces. They serve as structural proteins, receptors that link cells to matrix,³⁴ and comprise elements in supramolecular complexes within connective tissue.⁴² They also are important in inducing cellular differentiation and modulating growth factor action,43, 44, 45 and in producing the semipermeable properties of basement membrane.⁴⁶ In addition, proteoglycans produce a hydrated

Conclusion

The structural organization and expression of a number of specialized molecules that are involved in the growth and differentiation of bladder epithelium and the maintenance of impermeability are reviewed. A review of results from the published literature and of the data presented herein leads to the conclusion that, in IC, the urothelium of the bladder is following an aberrant differentiation program that leads to altered synthesis of several proteoglycans, cell adhesion and tight junction

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¹: Dr. Moldwin is a paid lecturer and consultant for Ortho-McNeil Pharmaceutical.

View full text

Pathophysiology of interstitial cystitisBladder Defense Molecules, Urothelial Differentiation, Urinary Biomarkers, and Interstitial Cystitis

Section snippets

Urothelium in interstitial cystitis

Biomarkers for interstitial cystitis

Structure and function of proteoglycans and glycosaminoglycans

Identification of proteoglycans expressed in normal bladder

Materials and methods

Results

Discussion

Conclusion

Urology

Urology

J Urol

Urology

J Urol

J Urol

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Arch Biochem Biophys

J Urol

J Urol

J Urol

Urology

J Urol

J Urol

Dev Biol

Int J Biochem Cell Biol

Semin Cancer Biol

J Biol Chem

Trends Cell Biol

Curr Opin Cell Biol

J Biol Chem

J Biol Chem

J Urol

Matrix

J Urol

FEBS Lett

Distinctive ultrastructural pathology of nonulcerative interstitial cystitis: new observations and their potential significance in pathogenesis

Urol Int

Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis

Br J Urol

Permeability properties of the intact mammalian bladder epithelium

Am J Physiol

Ultrastructural study of an antibody-stabilized bladder surface: a new perspective on the elusive glycosaminoglycan layer

World J Urol

Pathophysiology of interstitial cystitis
Bladder Defense Molecules, Urothelial Differentiation, Urinary Biomarkers, and Interstitial Cystitis