Abnormalities in osteoclastogenesis and decreased tumorigenesis in mice deficient for ovarian cancer G protein-coupled receptor 1.
Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown to be a proton sensing receptor in vitro. We have shown that OGR1 functions as a tumor metastasis suppressor gene when it is over-expressed in human prostate cancer cells in vivo. To examine the physiological functions of OGR1, we generated conditional OGR1 deficient mice by homologous recombination. OGR1 deficient mice were viable and upon gross-inspection appeared normal. Consistent with in vitro studies showing that OGR1 is involved in osteoclastogenesis, reduced osteoclasts were detected in OGR1 deficient mice. A pH-dependent osteoclasts survival effect was also observed. However, overall abnormality in the bones of these animals was not observed. In addition, melanoma cell tumorigenesis was significantly inhibited in OGR1 deficient mice. OGR1 deficient mice in the mixed background produced significantly less peritoneal macrophages when stimulated with thioglycolate. These macrophages also showed altered extracellular signal-regulated kinases (ERK) activation and nitric oxide (NO) production in response to lipopolysaccharide. OGR1-dependent pH responses assessed by cAMP production and cell survival in macrophages or brown fat cells were not observed, presumably due to the presence of other proton sensing receptors in these cells. Our results indicate that OGR1's role in osteoclastogenesis is not strong enough to affect overall bone development and its role in tumorigenesis warrants further investigation. The mice generated can be potentially used for several disease models, including cancers or osteoclast-related diseases.
Li
Hui
H
Department of Obstetrics and Gynecology, Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Wang
Dongmei
D
Singh
Lisam Shanjukumar
LS
Berk
Michael
M
Tan
Haiyan
H
Zhao
Zhenwen
Z
Steinmetz
Rosemary
R
Kirmani
Kashif
K
Wei
Gang
G
Xu
Yan
Y
D002001:Adipose Tissue, Brown / Q000002:abnormalities / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011859:Radiography; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology
C525539:GPR68 protein, mouse; D043562:Receptors, G-Protein-Coupled; D013864:Thioglycolates; D009569:Nitric Oxide