Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis

Takako Koga; Masanori Inui; Kazuya Inoue; Sunhwa Kim; Ayako Suematsu; Eiji Kobayashi; Toshio Iwata; Hiroshi Ohnishi; Takashi Matozaki; Tatsuhiko Kodama; Tadatsugu Taniguchi; Hiroshi Takayanagi; Toshiyuki Takai

doi:10.1038/nature02444

Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis

Nature. 2004 Apr 15;428(6984):758-63. doi: 10.1038/nature02444.

Authors

Takako Koga¹, Masanori Inui, Kazuya Inoue, Sunhwa Kim, Ayako Suematsu, Eiji Kobayashi, Toshio Iwata, Hiroshi Ohnishi, Takashi Matozaki, Tatsuhiko Kodama, Tadatsugu Taniguchi, Hiroshi Takayanagi, Toshiyuki Takai

Affiliation

¹ Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

PMID: 15085135
DOI: 10.1038/nature02444

Abstract

Costimulatory signals are required for activation of immune cells, but it is not known whether they contribute to other biological systems. The development and homeostasis of the skeletal system depend on the balance between bone formation and resorption. Receptor activator of NF-kappaB ligand (RANKL) regulates the differentiation of bone-resorbing cells, osteoclasts, in the presence of macrophage-colony stimulating factor (M-CSF). But it remains unclear how RANKL activates the calcium signals that lead to induction of nuclear factor of activated T cells c1, a key transcription factor for osteoclastogenesis. Here we show that mice lacking immunoreceptor tyrosine-based activation motif (ITAM)-harbouring adaptors, Fc receptor common gamma subunit (FcRgamma) and DNAX-activating protein (DAP)12, exhibit severe osteopetrosis owing to impaired osteoclast differentiation. In osteoclast precursor cells, FcRgamma and DAP12 associate with multiple immunoreceptors and activate calcium signalling through phospholipase Cgamma. Thus, ITAM-dependent costimulatory signals activated by multiple immunoreceptors are essential for the maintenance of bone homeostasis. These results reveal that RANKL and M-CSF are not sufficient to activate the signals required for osteoclastogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing*
Adaptor Proteins, Vesicular Transport / chemistry
Adaptor Proteins, Vesicular Transport / genetics
Adaptor Proteins, Vesicular Transport / metabolism*
Amino Acid Motifs
Animals
Bone Resorption
Bone and Bones / drug effects
Bone and Bones / physiology*
Calcium Signaling / drug effects
Carrier Proteins / metabolism*
Cell Differentiation / drug effects
Cells, Cultured
Gene Deletion
Homeostasis* / drug effects
Macrophage Colony-Stimulating Factor / pharmacology
Membrane Glycoproteins / metabolism*
Mice
Osteoclasts / cytology
Osteoclasts / drug effects
Osteoclasts / physiology
Osteogenesis / physiology
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Receptors, Cell Surface / metabolism
Receptors, IgG / chemistry
Receptors, IgG / genetics
Receptors, IgG / metabolism*
Receptors, Immunologic / chemistry
Receptors, Immunologic / genetics
Receptors, Immunologic / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Carrier Proteins
Membrane Glycoproteins
Oscar protein, mouse
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Receptors, Cell Surface
Receptors, IgG
Receptors, Immunologic
Tnfrsf11a protein, mouse
Tnfsf11 protein, mouse
Tyrobp protein, mouse
Macrophage Colony-Stimulating Factor