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.

Abstract

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.

• Authors: Kristen E Govoni, Jon E Wergedal, Lore Florin, Peter Angel, David J Baylink, Subburaman Mohan
• Journal: Endocrinology (Endocrinology) Vol. 148 Issue 12 Pg. 5706-15 (Dec 2007) ISSN: 0013-7227 [Print] United States
• PMID: 17717052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Collagen Type I
• Insulin-Like Growth Factor Binding Proteins
• RNA, Messenger
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II

Topics

• Animals
• Body Weight (genetics, physiology)
• Bone Density
• Bone Development (genetics, physiology)
• Bone and Bones (metabolism)
• Collagen Type I (genetics, metabolism, physiology)
• Female
• Gene Deletion
• Immunohistochemistry
• Insulin-Like Growth Factor Binding Proteins (genetics, metabolism, physiology)
• Insulin-Like Growth Factor I (genetics, metabolism, physiology)
• Insulin-Like Growth Factor II (genetics, metabolism, physiology)
• Male
• Mice
• Mice, Transgenic
• RNA, Messenger (genetics, metabolism)
• Radioimmunoassay
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis
• Tomography, X-Ray Computed