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J. Biol. Chem., Vol. 282, Issue 35, 25509-25516, August 31, 2007

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Constitutively Active Parathyroid Hormone Receptor Signaling in Cells in Osteoblastic Lineage Suppresses Mechanical Unloading-induced Bone Resorption^*

Noriaki Ono, Kazuhisa Nakashima¹, Ernestina Schipani^¶, Tadayoshi Hayata, Yoichi Ezura, Kunimichi Soma^||, Henry M. Kronenberg^¶, and Masaki Noda^**2

From the Department of Molecular Pharmacology, Medical Research Institute, 21st Century Center of Excellence Program for the Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, the ^||Department of Orthodontic Science, Graduate School, the ^**ABJS Integrated Action Initiative in JSPS Core to Core Program, and the Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo 101-0062, Japan and the ^¶Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Multiple signaling pathways participate in the regulation of bone remodeling, and pathological negative balance in the regulation results in osteoporosis. However, interactions of signaling pathways that act comprehensively in concert to maintain bone mass are not fully understood. We investigated roles of parathyroid hormone receptor (PTH/PTHrP receptor) signaling in osteoblasts in unloading-induced bone loss using transgenic mice. Hind limb unloading by tail suspension reduced bone mass in wild-type mice. In contrast, signaling by constitutively active PTH/PTHrP receptor (caPPR), whose expression was regulated by the osteoblast-specific Col1a1 promoter (Col1a1-caPPR), suppressed unloading-induced reduction in bone mass in these transgenic mice. In Col1a1-caPPR transgenic (Tg) mice, hind limb unloading suppressed bone formation parameters in vivo and mineralized nodule formation in vitro similarly to those observed in wild-type mice. In addition, serum osteocalcin levels and mRNA expression levels of type I collagen, Runx2 and Osterix in bone were suppressed by unloading in both wild-type mice and Tg mice. However, in contrast to unloading-induced enhancement of bone resorption parameters in wild-type mice, Col1a1-caPPR signaling suppressed, rather than enhanced, osteoclast number and osteoclast surface as well as urinary deoxypyridinoline excretion upon unloading. Col1a1-caPPR signaling also suppressed mRNA expression levels of RANK and c-fms in bone upon unloading. Although the M-CSF and monocyte chemoattractant protein 1 (MCP-1) mRNA levels were enhanced in control Tg mice, these levels were suppressed in unloaded Tg mice. These results indicated that constitutive activation of PTH/PTHrP receptor signaling in osteoblastic cells suppresses unloading-induced bone loss specifically through the regulation of osteoclastic activity.

Received for publication, November 21, 2006 , and in revised form, May 8, 2007.

^* This work was supported by grants-in-aid from the Japanese Ministry of Education (21st Century Center of Excellence (COE) Program, Frontier Research for Molecular Destruction and Reconstitution of Tooth and Bone, 17012008, 18109011, 18659438, 18123456), grants from the Japan Space forum NASDA and ABJS (Advanced Bone and Joint Science) Strategic Research Networks/Projects, in Japan Society for Promotion of Science 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.

¹ To whom correspondence may be addressed: 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo, Japan. Tel.: 81-3-5280-8067; Fax: 81-3-5280-8067; E-mail: kxn.mph{at}mri.tmd.ac.jp. ² To whom correspondence may be addressed: 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo, Japan. Tel.: 81-3-5280-8066; Fax: 81-3-5280-8066; E-mail: noda.mph{at}mri.tmd.ac.jp.

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