Osteopontin Deficiency Ameliorates Prostatic Fibrosis and Inflammation.

Petra Popovics,Kristen S Uchtmann,Asha Jain,William A Ricke,Hannah Ruetten,Chad M Vezina,Mark Cadena,Elise Schroeder,Kegan O Skalitzky

doi:10.3390/ijms222212461

Petra Popovics, Kristen S Uchtmann + Show 7 more

Open Access

https://doi.org/10.3390/ijms222212461

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Abstract

Fibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men. Our previous studies identified that osteopontin (OPN), a pro-fibrotic cytokine, is abundant in the prostate of men with LUTS, and its secretion is stimulated by inflammatory cytokines potentially to drive fibrosis. This study investigates whether the lack of OPN ameliorates inflammation and fibrosis in the mouse prostate. We instilled uropathogenic E. coli (UTI89) or saline (control) transurethrally to C57BL/6J (WT) or Spp1tm1Blh/J (OPN-KO) mice and collected the prostates one or 8 weeks later. We found that OPN mRNA and protein expression were significantly induced by E. coli-instillation in the dorsal prostate (DP) after one week in WT mice. Deficiency in OPN expression led to decreased inflammation and fibrosis and the prevention of urinary dysfunction after 8 weeks. RNAseq analysis identified that E. coli-instilled WT mice expressed increased levels of inflammatory and fibrotic marker RNAs compared to OPN-KO mice including Col3a1, Dpt, Lum and Mmp3 which were confirmed by RNAscope. Our results indicate that OPN is induced by inflammation and prolongs the inflammatory state; genetic blockade of OPN accelerates recovery after inflammation, including a resolution of prostate fibrosis.

Highlights

Substantial evidence has been accumulating on the crucial role of prostatic fibrosis in Lower urinary tract symptoms (LUTS) pathology, symptomology and therapeutic failure [21,22,24]
Prostatic fibrosis is triggered by inflammation, which occurs with high incidence in pathological prostate specimens [12,42,43]
Bacterial and autoimmune experimental prostatic inflammation models both present with a fibrosis component [18,19,44] which supports the inflammatory origin of prostatic fibrosis

Summary

Introduction

Lower urinary tract symptoms (LUTS) developing secondary to prostate disease are a constellation of multiple urinary voiding and irritative symptoms that deteriorate the quality of life [1]. The current LUTS patient population is expected to grow due to the increasing life expectancy [3]. Medical management of LUTS already poses an economic burden on our healthcare system, estimated to cost more than four billion dollars each year in the US [4]. Medical treatments for LUTS target benign prostatic hyperplasia (BPH) and smooth muscle dysfunction, yet 45% of patients still progress to surgery due to treatment resistance and side effects [5,6] which suggests the involvement of other pathological changes than what are currently recognized

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