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Inhibitory Immunoglobulin-Like Receptors LILRB and PIR-B Negatively Regulate Osteoclast Development¹

Yu Mori^*,, Sukenao Tsuji^*, Masanori Inui^*, Yuzuru Sakamoto^*, Shota Endo^*, Yumi Ito^*, Shion Fujimura^*, Takako Koga, Akira Nakamura^*, Hiroshi Takayanagi, Eiji Itoi and Toshiyuki Takai^2,*

^* Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Saitama, Japan; Department of Orthopedic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; and Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University and Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo, Japan

Osteoclasts, multinucleated cells of myeloid-monocytic origin, are responsible for bone resorption, which is crucial for maintenance of bone homeostasis in concert with bone-forming osteoblasts of nonhematopoietic, mesenchymal origin. Receptor activator of NF-B ligand (RANKL) and M-CSF, expressed on the surface of and secreted by osteoblasts, respectively, are essential factors that facilitate osteoclast formation. In contrast to the activation processes for osteoclast formation, inhibitory mechanisms for it are poorly understood. Herein we demonstrate that inhibitory Ig-like receptors recruiting Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) are expressed on osteoclast precursor cells like other myeloid cells, and that they play a regulatory role in the development of osteoclasts. We detected cell-surface expression of paired Ig-like receptor (PIR)-B and four isoforms of leukocyte Ig-like receptor (LILR)B on cultured osteoclast precursor cells of mouse and human origin, respectively, and showed that all of these ITIM-harboring inhibitory receptors constitutively recruit SHP-1 in the presence of RANKL and M-CSF, and that some of them can suppress osteoclast development in vitro. Fluorescence energy transfer analyses have suggested that the constitutive binding of either murine PIR-B or its human ortholog LILRB1 to MHC class I molecules on the same cell surface comprises one of the mechanisms for developmental regulation. These results constitute the first evidence of the regulation of osteoclast formation by cell-surface, ITIM-harboring Ig-like receptors. Modulation of these regulatory receptors may be a novel way to control various skeletal system disorders and inflammatory arthritis.

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 This work was supported in part by the Core Research for Evolutional Science and Technology Program of the Japan Science and Technology Agency, a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a grant from the 21st Century Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases.

² Address correspondence and reprint requests to Dr. Toshiyuki Takai, Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Sendai 980-8575, Japan. E-mail address: tostakai{at}idac.tohoku.ac.jp

³ Abbreviations used in this paper: RANKL, receptor activator of NF-B ligand; β₂m, β₂-microglobulin; BMM, bone marrow monocyte/macrophage-lineage cells; FcR, Fc receptor common subunit; FRET, fluorescence resonance energy transfer; LILR, leukocyte Ig-like receptor; MNC, multinucleated cells; MOC, multinucleated mature osteoclast; PIR, paired Ig-like receptor; POC, prefusion osteoclast; SHP-1, Src homology 2 domain-containing tyrosine phosphatase 1; SIRP, signal regulatory receptor; TRAP, tartrate-resistant acid phosphatase.

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