The clinical relevance of the ratio NGF/creatinine in urine as a biomarker for overactive bladder syndrome (OAB) diagnosis is a matter of debate. ProNGF, the precursor form of nerve growth factor (NGF) was recently found to possess degenerative roles by signalling through its receptor p75NTR. The present study aims to identify the changes in concentration of NGF and proNGF, and the soluble factors involved in their proteolysis in the urine of an aging female population with OAB.

Cross-sectional study in which urine samples were obtained from 20 females of 50-80 years of age with OAB and from 20 controls of the same age group. Analyses were carried out with highly specific ELISA and enzymatic kits. Participants completed a full clinical evaluation and validated self-reported questionnaires: Overactive Bladder Symptom Score (OABSS), International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and Incontinence Impact Questionnaire (IIQ-7),as well as a one-day voiding diary.

The average age in the OAB group was expectedly higher than control (68.9 ± 11.38 vs 56.25 ± 5.22 years in controls) (p<0.001). There was no significant difference in demographics and vital signs parameters between controls and OAB subjects. Total questionnaires’ scores reflecting OAB symptom severity and its impact on quality of life were significantly higher in the OAB group. (Table 1) NGF ELISA kit specificity was confirmed. We found that the proNGF/NGF ratio was significantly doubled in the OAB group. Enzymatic activity of MMP-7, the main enzyme responsible for extracellular maturation of proNGF, was significantly increased in the OAB group, however, this was counteracted by several-folds increase in the MMP-9 responsible for NGF proteolysis. On the other hand, nitric oxide and PGE2, two factors increasing expression and activity of MMP-9, also displayed higher concentrations in urine of OAB patients. (Table 1) Receiver operating characteristic (ROC) showed that proNGF/NGF ratio has high sensitivity for OAB diagnosis where the area under the curve was 0.731 (p= 0.08, 95% CI= 0.514-0.948).

The increase of proNGF/NGF ratio in OAB patients in aging female population could be a result of disturbances in the proteolytic activity. This increase could originate from the increased activity of MMP-9, enhancing NGF proteolysis in OAB. Local tissue factors in the bladder such as NO, ATP and PGE2 that increase due to metabolic stress can induce changes in proteolytic enzymes of proNGF/NGF which in turn can affect proNGF/NGF balance. Previous studies have focused on the inhibition of proNGF maturation as a principal lead to proNGF/NGF imbalance. However, in this report NGF degradation could equally contribute to proNGF/NGF imbalance in OAB.

The ratio ProNGF/NGF could constitute a more reliable biomarker for OAB rather than NGF level alone. Increased NGF degradation by MMP9 suggests that MMP9 inhibitors may constitute a new therapeutic target to explore for OAB.