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J. Biol. Chem., Vol. 283, Issue 28, 19400-19409, July 11, 2008

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Osteopontin Negatively Regulates Parathyroid Hormone Receptor Signaling in Osteoblasts^*

Noriaki Ono^¶, Kazuhisa Nakashima¹, Susan R. Rittling^||, Ernestina Schipani^**, Tadayoshi Hayata, Kunimichi Soma^¶, David T. Denhardt, Henry M. Kronenberg^**, Yoichi Ezura¹, and Masaki Noda^¶¶1

From the Department of Molecular Pharmacology, Medical Research Institute and 21st Century Center of Excellence Program for the Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, 2-3-10 Kanda-surugadai, Chiyoda-ku, 101-0062, Tokyo, Japan, ^¶Orthodontic Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8510, Tokyo, Japan, ^||The Forsyth Institute, Boston, Massachusetts 02115, ^**Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08701, Advanced Bone and Joint Science (ABJS) Integrated Action Initiative in Japan Society for the Promotion of Science Core to Core Program and ^¶¶Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan

Systemic hormonal control exerts its effect through the regulation of local target tissues, which in turn regulate upstream signals in a feedback loop. The parathyroid hormone (PTH) axis is a well defined hormonal signaling system that regulates calcium levels and bone metabolism. To understand the interplay between systemic and local signaling in bone, we examined the effects of deficiency of the bone matrix protein osteopontin (OPN) on the systemic effects of PTH specifically within osteoblastic cell lineages. Parathyroid hormone receptor (PPR) transgenic mice expressing a constitutively active form of the receptor (caPPR) specifically in cells of the osteoblast lineage have a high bone mass phenotype. In these mice, OPN deficiency further increased bone mass. This increase was associated with conversion of the major intertrabecular cell population from hematopoietic cells to stromal/osteoblastic cells and parallel elevations in histomorphometric and biochemical parameters of bone formation and resorption. Treatment with small interfering RNA (siRNA) for osteopontin enhanced H223R mutant caPPR-induced cAMP-response element (CRE) activity levels by about 10-fold. Thus, in addition to the well known calcemic feedback system for PTH, local feedback regulation by the bone matrix protein OPN also plays a significant role in the regulation of PTH actions.

Received for publication, January 2, 2008 , and in revised form, April 16, 2008.

^* 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 18109011, 18659438, 18123456, and 20013014) and grants from the Japan Space Forum, NASDA, and the Japan Society for Promotion of Science (JSPS Core to Core Program). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, 101-0062, 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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