Osteoclast inhibitory peptide-1 binding to the Fc gammaRIIB inhibits osteoclast differentiation.
Osteoclast inhibitory peptide-1 (OIP) is an autocrine/paracrine inhibitor of osteoclast differentiation, and mice that overexpress OIP-1 in osteoclast lineage cells develop an osteopetrosis bone phenotype. In this study, we show that OIP-1 binding to the Fc gamma receptor IIB (Fc gammaRIIB) inhibits osteoclast differentiation. Confocal microscopy revealed colocalization of OIP-1 with Fc gammaRIIB in osteoclasts, and we observed that OIP-1 carboxy-terminal GPI-linked peptide forms a 1:1 complex with recombinant Fc gammaRIIB protein with an affinity binding of a dissociation constant of approximately 4 microm. Immunoreceptor tyrosine-based activation motif (ITAM)-bearing adapter proteins (FcR gamma and DNAX-activating protein of molecular mass 12 kDa) are critical for osteoclast development, and OIP-1 transgenic mouse-derived preosteoclast cells demonstrated suppression (6-fold) of ITAM phosphorylation of FcR gamma but not DNAX-activating protein of molecular mass 12 kDa. Interestingly, these preosteoclast cells demonstrated increased levels (4-fold) of immunoreceptor tyrosine-based inhibitory motif phosphorylation of Fc gammaRIIB and Src homology 2-domain-containing proteins tyrosine phosphatase 1 activation. Further, OIP-1 mouse-derived preosteoclasts cells demonstrated inhibition of spleen tyrosine kinase activation (4.5-fold), compared with wild-type mice. These results suggest that cross-regulation of immunoreceptor tyrosine-based inhibitory motif and ITAM bearing Fc receptors may play a role in OIP-1 suppression of spleen tyrosine kinase activation and inhibition of osteoclast differentiation. Thus, OIP-1 is an important physiologic regulator of osteoclast development and may have therapeutic utility for bone diseases with high bone turnover.
Shanmugarajan
Srinivasan
S
Charles P. Darby Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, South Carolina 29425, USA.
Beeson
Craig C
CC
Reddy
Sakamuri V
SV
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034622:RNA Interference; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D000072377:Syk Kinase; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; C080571:Fc gamma receptor IIB; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C092282:PSMC5 protein, human; D017452:Receptors, IgG; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities