Heme Oxygenase-1 Is a Pivotal Modulator of Bone Turnover and Remodeling: Molecular Implications for Prostate Cancer Bone Metastasis

STARBUCK, MICHAEL; NAVONE, NORA; VAZQUEZ, ELBA; LABANCA, ESTEFANIA; GUERON, GERALDINE; ANSELMINO, NICOLÁS; COTIGNOLA, JAVIER; ZENCLUSSEN, ANA C.; LABANCA, ESTEFANIA; STARBUCK, MICHAEL; GUERON, GERALDINE; NAVONE, NORA; ANSELMINO, NICOLÁS; VAZQUEZ, ELBA; COTIGNOLA, JAVIER; ZENCLUSSEN, ANA C.

ANTIOXIDANTS & REDOX SIGNALING

MARY ANN LIEBERT INC

Lugar: New York; Año: 2020

1523-0864

Aims: Bone is the most frequent site of prostate cancer (PCa) metastasis. Tumor cells interact with the bone microenvironment interrupting tissue balance. Heme oxygenase-1 (HO-1; encoded by Hmox1) appears as a potential target in PCa maintaining the cellular homeostasis. Our hypothesis is that HO-1 is implicated in bone physiology and modulate the communication with PCa cells. Here we aimed at: 1) assessing the physiological impact of Hmox1 gene Knock-out (KO) on bone metabolism in vivo and 2) determining the alterations of the transcriptional landscape associated with tumorigenesis and bone remodeling in cells growing in co-culture (PCa cells with primary mouse osteoblasts -PMOs- from BALB/c Hmox1+/+, Hmox1+/- and Hmox1-/- mice).Results: Histomorphometric analysis of Hmox1-/- mice bones exhibited significantly decreased bone density with reduced remodeling parameters. A positive correlation between Hmox1 expression and Runx2, Col1a1, Csf1 and Opg genes was observed in PMOs. Flow cytometry studies revealed two populations of PMOs with different ROS levels. The high-ROS population was increased in PMOs Hmox1+/- compared with Hmox1+/+, but was significantly reduced in PMOs Hmox1-/-, suggesting restrained ROS tolerance in KO cells. Gene expression was altered in PMOs upon co-culture with PCa cells, showing a pro-osteoclastic profile. Moreover, HO-1 induction in PCa cells growing in co-culture with PMOs resulted in a significant modulation of key bone markers such as PTHrP and OPG. Innovation and Conclusion: We here demonstrate the direct implications of HO-1 expression in bone remodeling and how it participates in the alterations in the communication between bone and prostate tumor cells.