ALTERNATE SIGNALING PATHWAYS SELECTIVELY REGULATE BINDING OF INSULIN-LIKE-GROWTH-FACTOR-I AND INSULIN-LIKE-GROWTH-FACTOR-II ON FETAL-RAT BONE-CELLS

Bone cells synthesize and respond to ICF-I and ICF-II which contribute to bone remodeling and linear growth. In osteoblasts, prostaglandin ( PG)E-2 stimulates IGF-I but not IGF-II synthesis through a cAMP-depend ent protein kinase A (PKA)-related event. However, protein kinase C (P KC) activation by PGE(2) enhances replication and protein synthesis by less differentiated periosteal cells more so than in osteoblast-enric hed cultures from fetal rat bane. Using various PGs and other PKA and PKC pathway activators, the importance of these aspects of PGE(2) acti vity has now been examined on IGF receptors in these bone cell culture models. PGE(2) and other agents that activate PKA enhanced I-125-IGF- II binding to type 2 IGF receptors on both cell populations. In contra st, agents that activate PKC enhanced I-125-IGF-I binding to type 1 re ceptors on less differentiated bone cells, and of these, only phorbol myristate acetate (PMA), which activates PKC in a receptor-independent way, was effective in osteoblast-enriched cultures. No stimulator inc reased total type 1 receptor protein in either cell population. Conseq uently, ligand binding to type 1 and type 2 IGF receptors is different ially modulated by specific intracellular pathways in bone cells. Impo rtantly, changes in apparent type 1 receptor number occur rapidly and may do so at least in part through post-translational effects. These r esults may help to predict new ways to manipulate autocrine or paracri ne actions by IGFs in skeletal tissue. (C) 1998 Wiley-Liss, Inc.