TAK-778 induces osteogenesis in ovariectomized rats via an estrogen receptor-dependent pathway.
TAK-778, a derivative of ipriflavone, has been shown to induce bone growth both in vitro and in vivo. Recently, it has been shown that TAK-778 can enhance osteoblast differentiation of human bone marrow cells via an estrogen receptor (ER)-dependent pathway. However, the mechanism by which TAK-778 exerts its effect in vivo has not been determined. Considering the evidence that TAK-778 acts via ER-mediated signaling in vitro, in the present study we tested if TAK-778 induced osteogenesis via an ER-dependent pathway using an ovariectomized (OVX) rat model. Two weeks after test animals underwent ovariectomy, TAK-778 and/or tamoxifen was administered orally over 3 months. Vehicle-treated and sham-operated rats served as controls. The bone mineral density (BMD) of the lumbar vertebrae and sagittal two-dimensional images of the L3 vertebral body were measured. In addition, bone formation rates (BFR) and serum calcium and osteocalcin levels were measured. The results indicated that TAK-778 significantly increased BMD, serum calcium and osteocalcin levels, and BFR when compared to that of the vehicle-treated group. However, tamoxifen, a well-known ER antagonist, clearly inhibited the increase in these parameters induced by TAK-778. In addition, micro-computed tomography scans showed that treatment with TAK-778 increased the structure model index, bone volume/tissue volume, and trabecular thickness parameters and decreased the trabecular separation/spacing in OVX rats. Tamoxifen suppressed these effects when administered in combination with TAK-778. Taken together, the present study showed that TAK-778 enhanced bone formation in OVX rats and that this effect was dependent on an ER-mediated pathway.
Cai
Ming
M
The Tenth People's Hospital of Tongji University, Shanghai, 200027, People's Republic of China.
Yu
Yongchun
Y
Feng
Shengmei
S
Tao
Kun
K
Li
Shaohua
S
Deng
Lianfu
L
Cai
Zhengdong
Z
D000818:Animals; D001582:Benzothiepins / Q000494:pharmacology*; D015519:Bone Density / Q000187:drug effects; D005260:Female; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D051381:Rats; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014057:Tomography, X-Ray Computed
D001582:Benzothiepins; D011960:Receptors, Estrogen; C120450:TAK 778; D013629:Tamoxifen