title: Upregulation of osteoclast alpha2beta1 integrin compensates for lack of alphavbeta3 vitronectin receptor in Iraqi-Jewish-type Glanzmann thrombasthenia.
abstract: Osteoclasts utilize alphavbeta3 integrin adhesion to bone matrix during bone resorption. We have generated osteoclasts from the peripheral blood of Iraqi-Jewish patients with Glanzmann thrombasthenia (GT) who are completely deficient in beta3 integrin and exhibit a haemorrhagic diathesis resulting from the absence of platelet alphaIIbbeta3. We show that, in contrast to osteoclasts generated from normal subjects or patients with alphaIIb integrin deficiency, GT osteoclasts lack alphavbeta3. These osteoclasts exhibited a two- to fourfold increase in alpha2 and beta1 integrin expression, whereas other alphav integrins, including alphavbeta5, were not significantly affected. An accompanying decrease in bone resorption was observed, with 44% and 59% declines in pit number and depth, respectively, and resorption lacunae showed abnormal morphology on scanning electron microscopy. However, osteoclasts from GT developed in similar numbers to controls and exhibited an otherwise 'normal' phenotype. We conclude that the observed rise in alpha2beta1 expression compensates for the chronic genetic deficiency of alphavbeta3 in osteoclasts from patients with GT and is sufficient to enable bone resorption to proceed, albeit to a submaximal extent. This explains why Iraqi-Jewish patients with GT do not have osteopetrosis.
authors.affiliation: Departments of Medicine and Histopathology, University College London, London, UK. m.horton@ucla.ac.uk
authors.forename: Michael A
authors.initials: MA
authors.lastname: Horton
authors.forename: Helen M
authors.initials: HM
authors.lastname: Massey
authors.forename: Nurit
authors.initials: N
authors.lastname: Rosenberg
authors.forename: Brian
authors.initials: B
authors.lastname: Nicholls
authors.forename: Uri
authors.initials: U
authors.lastname: Seligsohn
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001862:Bone Resorption / Q000209:etiology / Q000378:metabolism; D001842:Bone and Bones / Q000648:ultrastructure; D002478:Cells, Cultured; D002648:Child; D005260:Female; D006801:Humans; D038982:Integrin alpha2beta1 / Q000097:blood*; D039302:Integrin alphaVbeta3 / Q000172:deficiency*; D008297:Male; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D010010:Osteoclasts / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D013915:Thrombasthenia / Q000097:blood* / Q000150:complications / Q000473:pathology; D015854:Up-Regulation
chemical_list: D038982:Integrin alpha2beta1; D039302:Integrin alphaVbeta3