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Recombinant Human Insulin-Like Growth Factor-Binding Protein-5 Stimulates Bone Formation Parameters in Vitro and in Vivo¹

J. L. Pettis Veterans Administration Medical Center and Loma Linda University (C.R., D.J.B., S.M.), Loma Linda, California 92357; and Roche Diagnostics Boehringer Mannheim GmbH, Pharma Research, Bone Metabolism, Am Nonnenwald (K.L., C.D.), D-82372 Penzberg, Germany

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

Insulin-like growth factor-binding protein-5 (rhIGFBP-5) is stored in bone and stimulates osteoblast cell proliferation in vitro. Bone formation is dependent on the number and activity of osteoblasts. We therefore evaluated the ability of recombinant human (rh) IGFBP-5 to increase osteoblast activity in vitro; both alkaline phosphatase (ALP) activity and osteocalcin levels showed a dose-dependent increase. In in vivo time-course studies, daily sc administration of 50 µg rhIGFBP-5/day/mouse significantly increased serum osteocalcin levels by day 7, and these levels were sustained through day 21. We further evaluated whether rhIGFBP-5 was as effective as IGF-I. Daily sc administration of rhIGFBP-5 (50 µg/day), IGF-I (13 µg/day), or IGF-I plus rhIGFBP-5 complex for 9 days increased serum osteocalcin levels by 58%, 65%, and 81% (P < 0.001 in all) and femoral bone extract ALP activity by 85% (P < 0.001), 29% (P < 0.05), and 13% (P = NS), respectively, and decreased carboxyl-terminal cross-linked telopeptide of type I collagen by 29% (P < 0.05), 20% (P = NS), and 12.5% (P = NS), respectively. One sc injection of rhIGFBP-5 (50 µg/mouse) increased serum osteocalcin and bone ALP activity by 21% (P < 0.05) and 27% (P < 0.02), respectively, after 5 days, but did not significantly increase serum IGF-I (1, 6, or 24 h/postinjection), suggesting that the effects of rhIGFBP-5 on bone are not mediated by increasing circulating IGF-I. Our data demonstrate that systemic administration of rhIGFBP-5, either alone or in combination with IGF-I, increases bone formation parameters in vivo.

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