Osteopontin deficiency leads to the resolution of prostatic fibrosis and inflammation

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.

Systems level identification of a matrisome-associated macrophage polarisation state in multi-organ fibrosis

“…Unlike Trem2, there is unequivocal evidence for the pro-fibrotic role of SPP1 during multi-organ fibrosis. Importantly, Spp1 deletion or neutralisation in mice attenuates fibrosis in different models of kidney, heart, lung, liver, skin, prostate, and muscle injuries ( Coombes et al, 2016 ; Dong and Ma, 2017 ; Honda et al, 2020 ; Kiefer et al, 2010 ; Kumar et al, 2022a ; Leung et al, 2013 ; Matsui et al, 2004 ; Persy et al, 2003 ; Popovics et al, 2021 ; Vetrone et al, 2009 ; Wu et al, 2012 ; Yoo et al, 2006 ). SPP1 is a constituent of ECM but can also be found as a secreted soluble factor.…”

Systems Level Identification of a Matrisome-Associated Macrophage Polarization State in Multi-Organ Fibrosis

“…Unlike Trem2, there is unequivocal evidence for the pro-fibrotic role of SPP1 during multi-organ fibrosis. Importantly, Spp1 deletion or neutralization in mice attenuates fibrosis in different models of kidney, heart, lung, liver, skin, prostate and muscle injuries [65][66][67][68][69][70][71][72][73][74][75][76]. Although SPP1 has also been described to be localized to non-myeloid cells [77], macrophage-derived SPP1 can induce migration and proliferation of fibroblasts [64].…”