PMID- 30811623
OWN - NLM
STAT- MEDLINE
DCOM- 20200113
LR  - 20200604
IS  - 1097-0045 (Electronic)
IS  - 0270-4137 (Print)
IS  - 0270-4137 (Linking)
VI  - 79
IP  - 7
DP  - 2019 May
TI  - Inhibition of the CXCL12/CXCR4 axis prevents periurethral collagen accumulation 
      and lower urinary tract dysfunction in vivo.
PG  - 757-767
LID - 10.1002/pros.23781 [doi]
AB  - BACKGROUND: Several studies show that prostatic fibrosis is associated with male 
      lower urinary tract dysfunction (LUTD). Development of fibrosis is typically 
      attributed to signaling through the transforming growth factor beta (TGF-beta) pathway, 
      but our laboratory has demonstrated that in vitro treatment of human prostatic 
      fibroblasts with the C-X-C motif chemokine ligand 12 (CXCL12) chemokine 
      stimulates myofibroblast phenoconversion and that CXCL12 has the capacity to 
      activate profibrotic pathways in these cells in a TGF-beta-independent manner. We 
      have previously reported that feeding mice high-fat diet (HFD) results in 
      obesity, type II diabetes, increased prostatic fibrosis, and urinary voiding 
      dysfunction. The purpose of this study was to test the hypothesis that in vivo 
      blockade of the CXCL12/CXCR4 axis would inhibit the development of 
      fibrosis-mediated LUTD in HFD-fed mice. METHODS: Two-month-old male 
      senescence-accelerated mouse prone-6 mice were fed either a HFD or low-fat diet 
      (LFD) for 8 months. Half of each dietary group were given constant access to 
      normal water or water that contained the C-X-C chemokine receptor type 4 (CXCR4; 
      CXCL12 receptor) antagonist CXCR4AIII. At the conclusion of the study, mice were 
      weighed, subjected to oral glucose tolerance testing and cystometry, and lower 
      urinary tract tissues collected and assessed for collagen content. RESULTS: 
      HFD-fed mice became significantly obese, insulin resistant, and hyperglycemic, 
      consistent with acquisition of metabolic syndrome, compared with LFD-fed mice. 
      Anesthetized cystometry demonstrated that HFD-fed mice experienced significantly 
      longer intercontractile intervals and greater functional bladder capacity than 
      LFD-fed mice. Immunohistochemistry demonstrated high levels of CXCR4 and CXCR7 
      staining in mouse prostate epithelial and stromal cells. Picrosirius red staining 
      indicated significantly greater periurethral collagen deposition in the prostates 
      of HFD than LFD-fed mice. Treatment with the CXCR4 antagonist CXCR4AIII did not 
      affect acquisition of metabolic syndrome but did reduce both urinary voiding 
      dysfunction and periurethral prostate collagen accumulation. CONCLUSIONS: This is 
      the first study to report that obesity-induced lower urinary tract fibrosis and 
      voiding dysfunction can be repressed by antagonizing the activity of the CXCR4 
      chemokine receptor in vivo. These data suggest that targeting the CXCL12/CXCR4 
      signaling pathway may be a clinical option for the prevention or treatment of 
      human male LUTD.
CI  - (c) 2019 Wiley Periodicals, Inc.
FAU - Macoska, Jill A
AU  - Macoska JA
AUID- ORCID: 0000-0001-8471-2221
AD  - Department of Biology, Center for Personalized Cancer Therapy, the University of 
      Massachusetts Boston, Boston, Massachusetts.
AD  - Department of Urology, George M. O'Brien Center for Urologic Research, Madison, 
      Wisconsin.
FAU - Wang, Zunyi
AU  - Wang Z
AD  - Department of Urology, George M. O'Brien Center for Urologic Research, Madison, 
      Wisconsin.
AD  - Department of Surgical Sciences, School of Veterinary Medicine, The University of 
      Wisconsin Madison, Madison, Wisconsin.
FAU - Virta, Johanna
AU  - Virta J
AD  - Department of Urology, George M. O'Brien Center for Urologic Research, Madison, 
      Wisconsin.
AD  - Department of Surgical Sciences, School of Veterinary Medicine, The University of 
      Wisconsin Madison, Madison, Wisconsin.
FAU - Zacharias, Nicholas
AU  - Zacharias N
AD  - Department of Urology, George M. O'Brien Center for Urologic Research, Madison, 
      Wisconsin.
AD  - Department of Surgical Sciences, School of Veterinary Medicine, The University of 
      Wisconsin Madison, Madison, Wisconsin.
FAU - Bjorling, Dale E
AU  - Bjorling DE
AD  - Department of Urology, George M. O'Brien Center for Urologic Research, Madison, 
      Wisconsin.
AD  - Department of Surgical Sciences, School of Veterinary Medicine, The University of 
      Wisconsin Madison, Madison, Wisconsin.
LA  - eng
GR  - U54 DK104310/DK/NIDDK NIH HHS/United States
GR  - U54DK04310/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190227
PL  - United States
TA  - Prostate
JT  - The Prostate
JID - 8101368
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (CXCR4 protein, mouse)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Cxcl12 protein, mouse)
RN  - 0 (Receptors, CXCR4)
RN  - 9007-34-5 (Collagen)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Chemokine CXCL12/antagonists & inhibitors/biosynthesis
MH  - Collagen/metabolism
MH  - Diet, High-Fat/adverse effects
MH  - Disease Models, Animal
MH  - Fibrosis/etiology/pathology
MH  - Lower Urinary Tract Symptoms/*drug therapy/etiology/physiopathology
MH  - Male
MH  - Metabolic Syndrome/etiology
MH  - Mice
MH  - Obesity/etiology
MH  - Prostate/*drug effects/pathology
MH  - Receptors, CXCR4/*antagonists & inhibitors/*biosynthesis
MH  - Signal Transduction/drug effects
PMC - PMC7269149
MID - NIHMS1016332
OTO - NOTNLM
OT  - diabetes
OT  - mouse
OT  - obesity
OT  - urinary
OT  - voiding
EDAT- 2019/02/28 06:00
MHDA- 2020/01/14 06:00
PMCR- 2020/06/03
CRDT- 2019/02/28 06:00
PHST- 2018/12/05 00:00 [received]
PHST- 2019/02/01 00:00 [revised]
PHST- 2019/02/07 00:00 [accepted]
PHST- 2019/02/28 06:00 [pubmed]
PHST- 2020/01/14 06:00 [medline]
PHST- 2019/02/28 06:00 [entrez]
PHST- 2020/06/03 00:00 [pmc-release]
AID - 10.1002/pros.23781 [doi]
PST - ppublish
SO  - Prostate. 2019 May;79(7):757-767. doi: 10.1002/pros.23781. Epub 2019 Feb 27.