Bone abnormalities in latent TGF-[beta] binding protein (Ltbp)-3-null mice indicate a role for Ltbp-3 in modulating TGF-[beta] bioavailability.
The TGF-betas are multifunctional proteins whose activities are believed to be controlled by interaction with the latent TGF-beta binding proteins (LTBPs). In spite of substantial effort, the precise in vivo significance of this interaction remains unknown. To examine the role of the Ltbp-3, we made an Ltbp-3-null mutation in the mouse by gene targeting. Homozygous mutant animals develop cranio-facial malformations by day 10. At 2 mo, there is a pronounced rounding of the cranial vault, extension of the mandible beyond the maxilla, and kyphosis. Histological examination of the skulls from null animals revealed ossification of the synchondroses within 2 wk of birth, in contrast to the wild-type synchondroses, which never ossify. Between 6 and 9 mo of age, mutant animals also develop osteosclerosis and osteoarthritis. The pathological changes of the Ltbp-3-null mice are consistent with perturbed TGF-beta signaling in the skull and long bones. These observations give support to the notion that LTBP-3 is important for the control of TGF-beta action. Moreover, the results provide the first in vivo indication for a role of LTBP in modulating TGF-beta bioavailability.
Dabovic
Branka
B
Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA. dabovb01@med.nyu.edu
Chen
Yan
Y
Colarossi
Cristina
C
Obata
Hiroto
H
Zambuto
Laura
L
Perle
Mary Ann
MA
Rifkin
Daniel B
DB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016723:Bone Remodeling; D001842:Bone and Bones / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019465:Craniofacial Abnormalities / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D018390:Gene Targeting; D017403:In Situ Hybridization; D053779:Latent TGF-beta Binding Proteins; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000150:complications / Q000235:genetics / Q000473:pathology; D010026:Osteosclerosis / Q000150:complications / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012886:Skull / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D053779:Latent TGF-beta Binding Proteins; C509039:Ltbp3 protein, mouse; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta