Role of extracellular matrix in insulin-like growth factor (IGF) binding protein-2 regulation of IGF-II action in normal human osteoblasts.
Insulin-like growth factor binding protein-2 (IGFBP-2) in its native form had little affinity for extracellular matrix (ECM) derived from human or rat osteoblastic cells. However, in the presence of IGFs, IGFBP-2 binding to ECM was markedly enhanced, with IGF-II being more effective than IGF-I. IGF-II-enhanced binding of IGFBP-2 to ECM was specific for IGFBP-2 of the six known IGFBPs. In the presence of IGF-II, IGFBP-2 bound with high affinity to heparin-Sepharose, but not to type I collagen, fibronectin, or laminin. Furthermore, heparin and heparan sulfate, but not chondroitin sulfate, inhibited IGFBP-2/IGF-II binding to ECM. High salt (100 mM NaCl) inhibited, while CaCl(2) enhanced binding of IGFBP-2/IGF-II to ECM. In the presence of ECM, IGFBP-2/IGF-II was as effective as IGF-II alone in stimulating [3H]thymidine and [3H]proline incorporation and in inhibiting apoptosis in cultured human osteoblasts. On the other hand, IGFBP-2 was a potent inhibitor of IGF-II action in human breast and ovarian carcinoma cells. There was no difference between soluble and ECM-associated IGFBP-2 in affinity for IGF-I and IGF-II. These data suggest a unique mechanism for targeting an anabolic IGFBP-2/IGF-II complex in bone.
Conover
Cheryl A
CA
Endocrine Research Unit, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. conover.cheryl@mayo.edu
Khosla
Sundeep
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000378:metabolism / Q000494:pharmacology*; D007797:Laminin / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011392:Proline / Q000378:metabolism; D051381:Rats; D013936:Thymidine / Q000378:metabolism
D024042:Collagen Type I; D005353:Fibronectins; D018971:Insulin-Like Growth Factor Binding Protein 2; D007797:Laminin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D006493:Heparin; D011392:Proline; D013936:Thymidine