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Loss of Osteopontin improves urinary function and alters the prostatic immune environment

  • Petra Popovics,
  • Kegan O. Skalitzky,
  • Elise Schroeder,
  • Asha Jain,
  • Chad M. Vezina,
  • William A. Ricke

Introduction and objective

Chronic inflammation in the prostate is associated with lower urinary tract symptoms (LUTS) in the aging men, but the molecular mechanism and its connection to steroid hormone imbalance are unknown. Our group is interested in osteopontin, a pro-inflammatory cytokine, which we previously demonstrated to be associated with the progression of LUTS. We previously demonstrated that OPN loss leads to accelerated healing of prostatic fibrosis and inflammation. The current study investigates whether prostatic OPN levels contribute to steroid hormone-induced lower urinary dysfunction and whether this action is directed via modulating the immune environment.

Methods

Lower urinary tract dysfunction (LUTD) was generated by the surgical implantation of pellets containing 25 mg testosterone (T) and 2.5 mg estradiol (E2) to male C57BL/6J (WT) or Spp1tm1Blh/J (OPN-KO) mice for two, six or twelve weeks. Urinary function was analyzed with void spot assay. OPN, collagen I and CD45 (immune cell marker) protein expression was investigated using immunohistochemistry (IHC).

Results

Steroid hormone treatment elevated OPN protein levels in the ventral prostate two weeks after pellet implantation. Normal urinary function was preserved in OPN-KO T+E2 mice until week four whereas WT mice acquired significantly increased voiding frequency just after two weeks. Prostate weights and bladder volumes were not significantly different in WT and OPN-KO mice at any of the time points indicating that obstruction had a similar course in these groups. In contrast, we observed significantly increased number of CD45 positive immune cells at week two and higher Col1a1 density at week twelve in WT but not in OPN-KO mice.

Conclusions

This is the first study demonstrating that hormonal imbalance regulate OPN expression in the prostate, which may contribute to increased voiding frequency. We also identified that the combination of testosterone and estradiol alters the immune environment in the prostate which may be the key pathological factor in the early stages of urinary dysfunction.

Source of Funding

This study was supported by grants from the National Institutes of Health including K12 DK100022-06 and K01 DK127150-01 (to P.P.) and U54 DK104310, R01 ES001332 (to W.A.R. and C.M.V.)