Journal
BONE
Volume 34, Issue 2, Pages 297-302Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2003.10.011
Keywords
pregnancy-associated plasma protein-A; insulin-like growth factor; cytokines; human osteoblasts
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Funding
- NIDDK NIH HHS [DK-07352] Funding Source: Medline
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Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase secreted by cultured human osteoblasts that has been implicated in the regulation of local insulin-like growth factor (IGF) bioavailability during bone growth and remodeling. However, very little is known about the regulation of PAPP-A expression in bone. In this study, we determined the effect of systemic and local osteoregulatory factors on PAPP-A mRNA and protein expression in normal human osteoblasts (hOB cells). Treatment of hOB cells with particular peptide growth factors (basic fibroblast growth factor, epidermal growth factor), steroid hormones (dexamethasone, 1,25-dihydroxyvitamin D-3) and cytokines [interleukin-6 (IL-6), IL-13, oncostatin M] with known involvement in bone cell physiology had no significant effect on PAPP-A expression. Agents that increase intracellular cyclic AMP (forskolin, prostaglandin E-2) increased PAPP-A mRNA and protein expression similar to 3-fold. Tumor necrosis factor alpha (TNFalpha), IL-1beta, and IL-4 also increased PAPP-A expression 3- to 4-fold. Transforming growth factor beta (TGFbeta) was previously shown to stimulate PAPP-A expression in hOB cells. The effects of TGFbeta, TNFalpha, and IL-1beta were additive, whereas the effects of TGFbeta and IL-4 were synergistic. In summary, TNFalpha, IL-1beta, and IL-4 were identified as potent stimulators of PAPP-A expression in primary cultures of human osteoblasts. These findings suggest a mechanism whereby cytokines present in bone and bone marrow could augment IGF bioavailability during skeletal growth and remodeling. (C) 2003 Elsevier Inc. All rights reserved.
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