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Submitted on February 15, 2006
Accepted on July 13, 2006
Department of Medicine, Endocrine Unit, Veterans Affairs Medical Center, and University of California, San Francisco, CA, USA; Mineralized Tissues Research Section, Hospital for Special Surgery, New York, NY, USA
* To whom correspondence should be addressed. E-mail: daniel.bikle{at}ucsf.edu.
Although insulin-like growth factor I (IGF-I) has been identified as an important growth factor for the skeleton, the role of IGF-I on embryonic bone development remains unknown. Here we show that in IGF-I deficient (IGF-I-/-) mice, skeletal malformations, including short-limbed dwarfism, were evident from 14.5 to 18.5 dpc, accompanied by delays of mineralization in the spinal column, sternum and fore paws. Reduced chondrocyte proliferation and increased chondrocyte apoptosis were identified in both the spinal ossification center and the growth plate of long bones. Abnormal chondrocyte differentiation and delayed initiation of mineralization was characterized by small size and fewer numbers of type X collagen expressing hypertrophic chondrocytes and lower osteocalcin expression. The Indian hedgehog (Ihh)- parathyroid hormone-related peptide (PTHrP) feedback loop was altered; expression of Ihh was reduced in IGF-I-/- mice in long bones and in the spine, whereas expression of PTHrP was increased. Our results indicate that IGF-I plays an important role in skeletal development by promoting chondrocyte proliferation and maturation, while inhibiting apoptosis to form bones of appropriate size and strength.
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