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Endocrinology Vol. 142, No. 6 2641-2648
Copyright © 2001 by The Endocrine Society

ARTICLES

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 Mechanism1

Naohisa Miyakoshi, Xuezhong Qin, Yuji Kasukawa, Charmaine Richman, Apurva K. Srivastava, David J. Baylink and Subburaman Mohan

Musculoskeletal Disease Center, J. L. Pettis Veterans Administration Medical Center (N.M., X.Q., Y.K., C.R., A.K.S., D.J.B., S.M.), Loma Linda, California 92357; and Departments of Medicine (X.Q., A.K.S., D.J.B., S.M.), Biochemistry (S.M.), and Physiology (S.M.), Loma Linda, California 92350

Address all correspondence and requests for reprints to: Subburaman Mohan, Ph.D., Musculoskeletal Disease Center (151), J. L. Pettis Veterans Administration Medical Center, 11201 Benton Street, Loma Linda, California 92357. E-mail: mohans{at}lom.med.va.gov

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.




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