Systemic administration of insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) increases bone formation parameters in mice by increasing IGF bioavailability via an IGFBP-4 protease-dependent mechanism.
Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) is a potent inhibitor of IGF actions in vitro. However, we found that systemic administration of IGFBP-4 at pharmacological doses caused a significant increase in bone formation parameters in mice by a mechanism that may involve increased IGF bioavailability via proteolysis of IGFBP-4. To evaluate the hypothesis that proteolysis of IGFBP-4 is essential for the stimulatory effects of systemically administered IGFBP-4, we produced wild-type, protease-resistant, and IGFBP-4 proteolytic fragments and evaluated their effects using biochemical markers. Protease-resistant IGFBP-4 was more potent than wild-type IGFBP-4 in inhibiting IGF-I-induced mouse osteoblast cell proliferation in vitro and in inhibiting IGF-I-induced increase in alkaline phosphatase (ALP) activity in bone extract after local administration in vivo. Systemic administration of wild-type IGFBP-4, but not protease-resistant IGFBP-4, increased serum osteocalcin, serum ALP, and ALP in skeletal extracts in a dose-dependent manner, with a maximal effect of 40% (P < 0.05) at 1.25 nmol/mouse. Systemic administration of wild-type, but not protease-resistant, IGFBP-4 increased free IGF-I levels in serum in normal mice. IGF-I, but not wild-type IGFBP-4, increased bone formation parameters in IGF-I-deficient mice. This study demonstrates that systemic administration of IGFBP-4 increases bone formation parameters in mice by increasing IGF bioavailability in the circulation via an IGFBP-4 protease-dependent mechanism.
Miyakoshi
N
N
Musculoskeletal Disease Center, J. L. Pettis Veterans Administration Medical Center, Loma Linda, California 92357, USA.
Qin
X
X
Kasukawa
Y
Y
Richman
C
C
Srivastava
A K
AK
Baylink
D J
DJ
Mohan
S
S
D000469:Alkaline Phosphatase / Q000097:blood / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology; D011266:Pregnancy-Associated Plasma Protein-A; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
D001786:Blood Glucose; 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; D008666:Metalloendopeptidases; D011266:Pregnancy-Associated Plasma Protein-A