Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast

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Abstract

Adiponectin, an adipose-derived hormone, exhibits various biological functions, such as increasing insulin sensitivity, protecting hypertension, and suppression of atherosclerosis, liver fibrosis, and tumor growth. Here, we report the role of adiponectin on bone metabolism. C57BL/6J mice were treated with adenovirus expressing lacZ or adiponectin, and their bones were analyzed by three-dimensional microcomputed tomography. Adiponectin-adenovirus treatment increased trabecular bone mass, accompanied by decreased number of osteoclasts and levels of plasma NTx, a bone-resorption marker. In vitro studies showed that adiponectin inhibited M-CSF- and RANKL-induced differentiation of mouse bone marrow macrophages and human CD14-positive mononuclear cells into osteoclasts and also suppressed the bone-resorption activity of osteoclasts. Furthermore, adiponectin enhanced mRNA expression of alkaline phosphatase and mineralization activity of MC3T3-E1 osteoblasts. Our results indicate that adiponectin exerts an activity to increase bone mass by suppressing osteoclastogenesis and by activating osteoblastogenesis, suggesting that adiponectin manipulation could be therapeutically beneficial for patients with osteopenia.

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Materials and methods

Animals. All animals were purchased from Clea Japan (Tokyo, Japan) and housed in a room under controlled temperature (23 ± 1 °C) and humidity (45–65%), and had free access to water and chow (Oriental Yeast). All animal experiments were conducted in accordance with the Institutional Guidelines for the Care and Use of laboratory animals.

Adiponectin adenovirus. Adenovirus producing the full-length mouse adiponectin was prepared as described previously [27]. Then, 2 × 108 plaque-forming units of

Adenovirus-mediated overexpression of adiponectin in vivo

To investigate the in vivo role of adiponectin in bone metabolism, we treated C57BL/6J mice with adenovirus producing adiponectin (Ad-adipo) or lacZ (Ad-lacZ). Two weeks after injection, we estimated structural changes in the bone by analyzing cortical and trabecular bones with 3D-μCT. Fig. 1A shows representative 3D-μCT images of the proximal tibia of Ad-lacZ- and Ad-adipo-treated mice, demonstrating a significantly larger trabecular bone volume in Ad-adipo-treated mice than in Ad-lacZ-treated

Discussion

In the present study, we investigated the role of adiponectin on bone formation in vivo, using an adiponectin-producing adenovirus. The major finding of the present study was that adiponectin supplement increased bone mass in trabecular bone. Analysis of the mechanism of this action revealed that adiponectin acts by reducing the differentiation and bone-resorption activity of osteoclasts, and possibly by enhancing the differentiation and mineralization activity of osteoblasts.

We observed the

Acknowledgments

We are grateful to F. Ikeda, R. Nishimura, T. Yoneda, and K. Sudo for the excellent technical assistance. We thank all members of Shimomura’s laboratory for the helpful discussion and comments. This study was supported in part by Yamanouchi Pharmaceutical Co., Ltd., Suzuken Memorial Foundation, The Tokyo Biochemical Research Foundation, Takeda Medical Research Foundation, Uehara Memorial Foundation, Takeda Science Foundation, Novartis Foundation (Japan) for the Promotion of Science, The Cell

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    These two authors contributed equally to this work.

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