Prostate-specific antigen induces apoptosis of osteoclast precursors: potential role in osteoblastic bone metastases of prostate cancer.
BACKGROUND
Prostate cancer is frequently associated with bone metastases with marked osteoblastic changes and low osteoclastic activity but its mechanism is not well understood. We previously reported that prostate-specific antigen (PSA) stimulated the proliferation and the activation of osteoblasts. In this study, we investigated the effect of PSA on osteoclastogenesis.


METHODS
Two human prostate cancer cell lines and PSA were directly injected into human adult bone (HAB) implanted into NOD/SCID mice, followed by morphological analysis. RAW 264.7 cells, murine osteoclast precursor, were treated with PSA.


RESULTS
PSA-producing LNCaP and PSA caused a significant decrease of osteoclast precursors and osteoclasts in HAB accompanied by osteoblast proliferation and new bone formation, while PSA-nonproducing PC3 showed increasing osteoclasts with osteolysis. PSA induced apoptosis of RAW 264.7 cells in vitro. PSA-induced apoptosis was dependent of enzymatic activity of PSA and was specific to immature tartrate-resistant acid phosphatase-negative mononuclear RAW 264.7 cells.


CONCLUSIONS
PSA plays a crucial role for osteoblastic bone metastasis by promoting both osteoblasts proliferation and apoptosis of osteoclast precursors.
Goya
Masato
M
Pathology Division, National Cancer Center Research Institute East, Chiba, Japan.
Ishii
Genichiro
G
Miyamoto
Shinichi
S
Hasebe
Takahiro
T
Nagai
Kanji
K
Yonou
Hiroyuki
H
Hatano
Tadashi
T
Ogawa
Yoshihide
Y
Ochiai
Atsushi
A
D000230:Adenocarcinoma / Q000556:secondary*; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D016025:Bone Transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D010006:Osteoblasts / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology*; D017430:Prostate-Specific Antigen / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013234:Stem Cells / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; D017430:Prostate-Specific Antigen