Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption.
In this study, we establish that the tyrosine kinase Syk is essential for osteoclast function in vitro and in vivo. Syk(-/-) osteoclasts fail to organize their cytoskeleton, and, as such, their bone-resorptive capacity is arrested. This defect results in increased skeletal mass in Syk(-/-) embryos and dampened basal and stimulated bone resorption in chimeric mice whose osteoclasts lack the kinase. The skeletal impact of Syk deficiency reflects diminished activity of the mature osteoclast and not impaired differentiation. Syk regulates bone resorption by its inclusion with the alpha v beta3 integrin and c-Src in a signaling complex, which is generated only when alpha v beta3 is activated. Upon integrin occupancy, c-Src phosphorylates Syk. Alpha v beta3-induced phosphorylation of Syk and the latter's capacity to associate with c-Src is mediated by the immunoreceptor tyrosine-based activation motif (ITAM) proteins Dap12 and FcRgamma. Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and alpha v beta3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target.
Zou
Wei
W
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kitaura
Hideki
H
Reeve
Jennifer
J
Long
Fanxin
F
Tybulewicz
Victor L J
VL
Shattil
Sanford J
SJ
Ginsberg
Mark H
MH
Ross
F Patrick
FP
Teitelbaum
Steven L
SL
D020816:Amino Acid Motifs; D000818:Animals; D001862:Bone Resorption / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation; D002678:Chimera / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D016415:Sequence Alignment; D000072377:Syk Kinase
D039302:Integrin alphaVbeta3; D047908:Intracellular Signaling Peptides and Proteins; D011971:Receptors, Immunologic; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse