TAK-778 induces osteogenesis in ovariectomized rats via an estrogen receptor-dependent pathway |
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Authors: | Ming Cai Yongchun Yu Shengmei Feng Kun Tao Shaohua Li Lianfu Deng Zhengdong Cai |
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Institution: | (1) The Tenth People’s Hospital of Tongji University, Shanghai, 200027, People’s Republic of China;(2) Department of Orthopaedics, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China; |
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Abstract: | 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. |
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