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J. Biol. Chem., Vol. 280, Issue 34, 30192-30200, August 26, 2005

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Unloading Induces Osteoblastic Cell Suppression and Osteoclastic Cell Activation to Lead to Bone Loss via Sympathetic Nervous System^*

Hisataka Kondo, Akira Nifuji, Shu Takeda¶, Yoichi Ezura, Susan R. Rittling||, David T. Denhardt||, Kazuhisa Nakashima, Gerard Karsenty¶, and Masaki Noda**

From the Department of Molecular Pharmacology, the 21st Century Center of Excellence Program for the Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, the ^**ABJS Integrated Action Initiative in JSPS Core to Core Program, and Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo 101-0062, Japan, ^¶Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, and ^||Rutgers University, Rutgers, New Jersey 08854

Osteoporosis is one of the major health problems in our modern world. Especially, disuse (unloading) osteoporosis occurs commonly in bedridden patients, a population that is rapidly increasing due to aging-associated diseases. However, the mechanisms underlying such unloading-induced pathological bone loss have not yet been fully understood. Since sympathetic nervous system could control bone mass, we examined whether unloading-induced bone loss is controlled by sympathetic nervous tone. Treatment with -blocker, propranolol, suppressed the unloading-induced reduction in bone mass. Conversely, -agonist, isoproterenol, reduced bone mass in loaded mice, and under such conditions, unloading no longer further reduced bone mass. Analyses on the cellular bases indicated that unloading-induced reduction in the levels of osteoblastic cell activities, including mineral apposition rate, mineralizing surface, and bone formation rate, was suppressed by propranolol treatment and that isoproterenol-induced reduction in these levels of bone formation parameters was no longer suppressed by unloading. Unloading-induced reduction in the levels of mineralized nodule formation in bone marrow cell cultures was suppressed by propranolol treatment in vivo. In addition, loss of a half-dosage in the dopamine -hydroxylase gene suppressed the unloading-induced bone loss and reduction in mineralized nodule formation. Unloading-induced increase in the levels of osteoclastic activities such as osteoclast number and surface as well as urinary deoxypyridinoline was all suppressed by the treatment with propranolol. These observations indicated that sympathetic nervous tone mediates unloading-induced bone loss through suppression of bone formation by osteoblasts and enhancement of resorption by osteoclasts.

Received for publication, April 18, 2005

^* This work was supported by grants-in-aid received from the Japanese Ministry of Education (21st Century Center of Excellence Program, Molecular Destruction and Reconstitution of Tooth and Bone, Grants 14207056, 16659405, 16027215, and 16022221) and grants from the Japan Space forum, NASDA, and the Japan Society for Promotion of Science (JSPS Core to Core Program, Research for the Future Program, Genome Science). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10 Kanda-Surugadai, 2-chome, Chiyoda-ku, Tokyo 101-0062, Japan. Tel.: 81-3-5280-8066; Fax: 81-3-5280-8066; E-mail: noda.mph{at}mri.tmd.ac.jp.

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