Effects of recombinant insulin-like growth factor-binding protein-4 on bone formation parameters in mice.
Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4), one of the most abundant IGFBPs produced by bone cells, is a potent inhibitor of IGF actions in vitro. To evaluate the modulation of IGF actions on bone formation in vivo by IGFBP-4, we produced intact and fragment (50- to 100-fold reduced IGF affinity) forms of BP-4 and examined their local and systemic effects using biochemical markers. Local administration of IGF-I over the right parietal bone significantly increased bone extract alkaline phosphatase activity; this was completely blocked by an equimolar dose of intact IGFBP-4, but not IGFBP-4 fragment. A single sc administration of IGF-I (2 microg/g BW) significantly increased bone formation markers in both serum and skeletal extracts; surprisingly, so did intact IGFBP-4, but not fragment IGFBP-4. Subcutaneous administration of an equimolar dose of IGFBP-4 along with IGF-I did not significantly block the IGF-I effect. Administration of intact IGFBP-4 significantly increased the serum 50-kDa IGF pool and decreased the 150-kDa IGF pool without significantly changing total IGF-I. We postulate that the increase in the 50-kDa IGF pool might enhance IGFs bioavailability via a mechanism involving IGFBP-4-specific protease. This study demonstrates for the first time that a single local administration of IGFBP-4 inhibits IGF-I-induced increases in bone formation, whereas systemic administration of IGFBP-4 alone increases serum levels of bone formation markers.
Miyakoshi
N
N
Musculoskeletal Disease Center, J. L. Pettis Veterans Administration Medical Center, Loma Linda, California 92357, USA.
Richman
C
C
Qin
X
X
Baylink
D J
DJ
Mohan
S
S
D000469:Alkaline Phosphatase / Q000097:blood / Q000378:metabolism; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000201:enzymology; D005260:Female; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D015675:Osteocalcin / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
D018974:Insulin-Like Growth Factor Binding Protein 4; D010446:Peptide Fragments; D011994:Recombinant Proteins; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D000469:Alkaline Phosphatase