Conditional deletion of insulin-like growth factor-I in collagen type 1alpha2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion.
IGF-I acts through endocrine and local, autocrine/paracrine routes. Disruption of both endocrine and local IGF-I action leads to neonatal lethality and impaired growth in various tissues including bone; however, the severity of growth and skeletal phenotype caused by disruption of endocrine IGF-I action is far less than with total IGF-I disruption. Based on these data and the fact that bone cells express IGF-I in high abundance, we and others predicted that locally produced IGF-I is also critical in regulating growth and bone accretion. To determine the role of local IGF-I, type 1alpha2 collagen-Cre mice were crossed with IGF-I loxP mice to generate Cre+ (conditional mutant) and Cre- (control) loxP homozygous mice. Surprisingly, approximately 40-50% of the conditional mutants died at birth, which is similar to total IGF-I disruption, but not observed in mice lacking circulating IGF-I. Expression of IGF-I in bone and muscle but not liver and brain was significantly decreased in the conditional mutant. Accordingly, circulating levels of serum IGF-I were also not affected. Disruption of local IGF-I dramatically reduced body weight 28-37%, femur areal bone mineral density 10-25%, and femur bone size 18-24% in growing mice. In addition, mineralization was reduced as early as during embryonic development. Consistently, histomorphometric analysis determined impaired osteoblast function as demonstrated by reduced mineral apposition rate (14-30%) and bone formation rate (35-57%). In conclusion, both local and endocrine IGF-I actions are involved in regulating growth of various tissues including bone, but they act via different mechanisms.
Govoni
Kristen E
KE
Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, 11201 Benton Street, Loma Linda, CA 92357, USA.
Wergedal
Jon E
JE
Florin
Lore
L
Angel
Peter
P
Baylink
David J
DJ
Mohan
Subburaman
S
D000818:Animals; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D015519:Bone Density; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D007150:Immunohistochemistry; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014057:Tomography, X-Ray Computed
D024042:Collagen Type I; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II
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