Impaired bone formation in transgenic mice resulting from altered integrin function in osteoblasts.
To determine the role of integrins in mature osteoblasts in vivo, we expressed in transgenic mice a dominant-negative integrin subunit (beta1-DN) consisting of the beta1 subunit cytoplasmic and transmembrane domains, driven by the osteoblast-specific osteocalcin promoter. Immature osteoblasts isolated from transgenic animals differentiated normally in vitro until the osteocalcin promoter became active; thereafter they detached from the substratum, suggesting that beta1-DN was impairing adhesion in mature osteoblasts. Transgenic animals had reduced bone mass, with increased cortical porosity in long bones and thinner flat bones in the skull. At 35 days, the rate of bone formation was reduced in cortical bone, and the parietal bones were 45% thinner than in wild-type animals. Active osteoblasts were less polar and had larger areas of cytoplasm with intracellular stores of matrix molecules. Osteocyte lacunae appeared normal around the cell body but did not have normal canilicular structures. At 90 days, the parietal bone of transgenic males was of normal width, suggesting that the original defect in matrix deposition had been repaired or compensated for. In contrast, transgenic females still had decreased bone mass in the parietal bone at 90 days. The decreased bone mass in TG females was accompanied by increased staining for osteoclast activity, suggesting that there was a sex-specific defect in mature animals.
Zimmerman
D
D
Department of Stomatology, University of California at San Francisco, San Francisco, California 94143-0512, USA.
Jin
F
F
Leboy
P
P
Hardy
S
S
Damsky
C
C
D000818:Animals; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000002:abnormalities; D002448:Cell Adhesion; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D066298:In Vitro Techniques; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000473:pathology / Q000502:physiology*; D015675:Osteocalcin / Q000235:genetics; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
D019012:Integrin beta1; D015675:Osteocalcin