Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane.
Effects of aromatase inhibitors (AIs) on the human skeletal system due to systemic estrogen depletion are becoming clinically important due to their increasing use as an adjuvant therapy in postmenopausal women with breast cancer. However, possible effects of AIs on human bone cells have remained largely unknown. We therefore studied effects of AIs including the steroidal AI, exemestane (EXE), and non-steroidal AIs, Aromatase Inhibitor I (AI-I) and aminoglutethimide (AGM), on a human osteoblast. We employed a human osteoblast cell line, hFOB, which maintains relatively physiological status of estrogen and androgen pathways of human osteoblasts, i.e., expression of aromatase, androgen receptor (AR), and estrogen receptor (ER) beta. We also employed osteoblast-like cell lines, Saos-2 and MG-63 which expressed aromatase, AR, and ERalpha/beta in order to further evaluate the mechanisms of effects of AIs on osteoblasts. There was a significant increment in the number of the cells following 72 h treatment with EXE in hFOB and Saos-2 but not in MG-63, in which the level of AR mRNA was lower than that in hFOB and Saos-2. Alkaline phosphatase activity was also increased by EXE treatment in hFOB and Saos-2. Pretreatment with the AR blocker, flutamide, partially inhibited the effect of EXE. AI-I exerted no effects on osteoblast cell proliferation and AGM diminished the number of the cells. hFOB converted androstenedione into E2 and testosterone (TST). Both EXE and AI-I decreased E2 level and increased TST level. In a microarray analysis, gene profile patterns following treatment with EXE demonstrated similar patterns as with DHT but not with E2 treatment. The genes induced by EXE treatment were related to cell proliferation, differentiation which includes genes encoding cytoskeleton proteins. We also examined the expression levels of these genes using quantitative RT-PCR in hFOB and Saos-2 treated with EXE and DHT and with/without flutamide. HOXD11 gene known as bone morphogenesis factor and osteoblast growth-related genes were induced by EXE treatment as well as DHT treatment in both hFOB and Saos-2. These results indicated that the steroidal aromatase inhibitor, EXE, stimulated hFOB cell proliferation via both AR dependent and independent pathways.
Miki
Yasuhiro
Y
Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
Suzuki
Takashi
T
Hatori
Masahito
M
Igarashi
Katsuhide
K
Aisaki
Ken-ich
KI
Kanno
Jun
J
Nakamura
Yasuhiro
Y
Uzuki
Miwa
M
Sawai
Takashi
T
Sasano
Hironobu
H
D000469:Alkaline Phosphatase / Q000378:metabolism; D000616:Aminoglutethimide / Q000737:chemistry / Q000494:pharmacology; D000730:Androstadienes / Q000737:chemistry / Q000494:pharmacology*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004958:Estradiol / Q000096:biosynthesis; D005485:Flutamide / Q000737:chemistry / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis; D045165:Testosterone Congeners / Q000737:chemistry / Q000494:pharmacology
C410798:AR protein, human; D000730:Androstadienes; D047072:Aromatase Inhibitors; D017931:DNA Primers; D012333:RNA, Messenger; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D000616:Aminoglutethimide; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; D000469:Alkaline Phosphatase; C056516:exemestane