Ly49Q, an ITIM-bearing NK receptor, positively regulates osteoclast differentiation.
Osteoclasts, multinucleated cells that resorb bone, play a key role in bone remodeling. Although immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling is critical for osteoclast differentiation, the significance of immunoreceptor tyrosine-based inhibitory motif (ITIM) has not been well understood. Here we report the function of Ly49Q, an Ly49 family member possessing an ITIM motif, in osteoclastogenesis. Ly49Q is selectively induced by receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) stimulation in bone marrow-derived monocyte/macrophage precursor cells (BMMs) among the Ly49 family of NK receptors. The knockdown of Ly49Q resulted in a significant reduction in the RANKL-induced formation of tartrate-resistance acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a decreased expression of osteoclast-specific genes such as Nfatc1, Tm7sf4, Oscar, Ctsk, and Acp5. Osteoclastogenesis was also significantly impaired in Ly49Q-deficient cells in vitro. The inhibitory effect of Ly49Q-deficiency may be explained by the finding that Ly49Q competed for the association of Src-homology domain-2 phosphatase-1 (SHP-1) with paired immunoglobulin-like receptor-B (PIR-B), an ITIM-bearing receptor which negatively regulates osteoclast differentiation. Unexpectedly, Ly49Q deficiency did not lead to impaired osteoclast formation in vivo, suggesting the existence of a compensatory mechanism. This study provides an example in which an ITIM-bearing receptor functions as a positive regulator of osteoclast differentiation.
Hayashi
Mikihito
M
Department of Cell Signaling, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan.
Nakashima
Tomoki
T
Kodama
Tatsuhiko
T
Makrigiannis
Andrew P
AP
Toyama-Sorimachi
Noriko
N
Takayanagi
Hiroshi
H
D020816:Amino Acid Motifs; D000818:Animals; D002454:Cell Differentiation; D055785:Gene Knockdown Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000096:biosynthesis* / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000378:metabolism; D034622:RNA Interference
C527089:Klra17 protein, mouse; D016328:NF-kappa B; D055650:NK Cell Lectin-Like Receptor Subfamily A; D053245:RANK Ligand