A Glanzmann's mutation in beta 3 integrin specifically impairs osteoclast function.
Osteoclastic bone resorption requires cell-matrix contact, an event mediated by the alpha v beta 3 integrin. The structural components of the integrin that mediate osteoclast function are, however, not in hand. To address this issue, we generated mice lacking the beta 3 integrin gene, which have dysfunctional osteoclasts. Here, we show the full rescue of beta 3(-/-) osteoclast function following expression of a full-length beta 3 integrin. In contrast, truncated beta 3, lacking a cytoplasmic domain (h beta 3c), is completely ineffective in restoring function to beta 3(-/-) osteoclasts. To identify the components of the beta 3 cytoplasmic domain regulating osteoclast function, we generated six point mutants known, in other circumstances, to mediate beta integrin signaling. Of the six, only the S(752)P substitution, which also characterizes a form of the human bleeding disorder Glanzmann's thrombasthenia, fails to rescue beta 3(-/-) osteoclasts or restore ligand-activated signaling in the form of c-src activation. Interestingly, the double mutation Y(747)F/Y(759)F, which disrupts platelet function, does not affect the osteoclast. Thus similarities and distinctions exist in the mechanisms by which the beta 3 integrin regulates platelets and osteoclasts.
Feng
X
X
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.
Novack
D V
DV
Faccio
R
R
Ory
D S
DS
Aya
K
K
Boyer
M I
MI
McHugh
K P
KP
Ross
F P
FP
Teitelbaum
S L
SL
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001862:Bone Resorption / Q000235:genetics*; D048429:Cell Size; D003599:Cytoskeleton / Q000473:pathology; D039661:Integrin beta3; D016023:Integrins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010980:Platelet Membrane Glycoproteins / Q000235:genetics*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013915:Thrombasthenia / Q000235:genetics*
D015703:Antigens, CD; D039661:Integrin beta3; D016023:Integrins; D010980:Platelet Membrane Glycoproteins; D016392:Proto-Oncogene Proteins pp60(c-src)