Dwarfism in mice lacking collagen-binding integrins α2β1 and α11β1 is caused by severely diminished IGF-1 levels.
Mice with a combined deficiency in the α2β1 and α11β1 integrins lack the major receptors for collagen I. These mutants are born with inconspicuous differences in size but develop dwarfism within the first 4 weeks of life. Dwarfism correlates with shorter, less mineralized and functionally weaker bones that do not result from growth plate abnormalities or osteoblast dysfunction. Besides skeletal dwarfism, internal organs are correspondingly smaller, indicating proportional dwarfism and suggesting a systemic cause for the overall size reduction. In accordance with a critical role of insulin-like growth factor (IGF)-1 in growth control and bone mineralization, circulating IGF-1 levels in the sera of mice lacking either α2β1 or α11β1 or both integrins were sharply reduced by 39%, 64%, or 81% of normal levels, respectively. Low hepatic IGF-1 production resulted from diminished growth hormone-releasing hormone expression in the hypothalamus and, subsequently, reduced growth hormone expression in the pituitary glands of these mice. These findings point out a novel role of collagen-binding integrin receptors in the control of growth hormone/IGF-1-dependent biological activities. Thus, coupling hormone secretion to extracellular matrix signaling via integrins represents a novel concept in the control of endocrine homeostasis.
Department of Dermatology, University of Cologne, 50937 Cologne, Germany.
Katrin
K
Blumbach
Anja
A
Niehoff
Bengt F
BF
Belgardt
Harald W A
HW
Ehlen
Markus
M
Schmitz
Ralf
R
Hallinger
Jan-Niklas
JN
Schulz
Jens C
JC
Brüning
Thomas
T
Krieg
Markus
M
Schubert
Donald
D
Gullberg
Beate
B
Eckes
D000818:Animals; D015519:Bone Density / Q000235:genetics; D001842:Bone and Bones / Q000166:cytology / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D004392:Dwarfism / Q000235:genetics* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D013006:Growth Hormone / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D038982:Integrin alpha2beta1 / Q000235:genetics*; D016023:Integrins / Q000235:genetics*; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000502:physiology; D038981:Receptors, Collagen / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology
D038982:Integrin alpha2beta1; D016023:Integrins; D038981:Receptors, Collagen; C467800:integrin alpha11beta1; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003094:Collagen; D013007:Growth Hormone-Releasing Hormone