Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production.
Osteoclast-mediated bone resorption plays a crucial role in osseous remodeling. Osteoblasts are important regulators of this activity, in part through their ability to produce osteoclast-regulating soluble factors such as interleukin-6 (IL-6). IL-11 is a newly appreciated pleotropic cytokine whose spectrum of biological activities overlaps with that of IL-6. As a result, we hypothesized that osteoblasts are an important skeletal source of this cytokine. To test this hypothesis, we characterized the IL-11 production of unstimulated and stimulated SaOS-2 human osteosarcoma cells. Unstimulated cells produced modest amounts of IL-11. The osteotropic agents recombinant IL-1 (0.25-5 ng/ml), transforming growth factor-beta 1 (0.1-10 ng/ml), PTH (10(-8)-10(-11) M), and PTH-related peptide ((10(-8)-10-11 M) further increased SaOS-2 cell IL-11 protein production and messenger RNA accumulation. These stimulatory effects were dose and time dependent, and the IL-11 that was produced was bioactive, as demonstrated by its ability to stimulate the proliferation of T10D plasmacytoma cells. The protein kinase-C activator, 12-O-Tetra-decanoylphorbol 13-acetate, and a variety of cAMP agonists [forskolin, prostaglandin E1, prostaglandin E2, and (Bu)2AMP] also stimulated osteoblast IL-11 protein production and messenger RNA accumulation. In contrast, recombinant IL-4, recombinant interferon-gamma, and endotoxin did not stimulate SaOS-2 cells in a similar fashion. Importantly, the ability to produce IL-11 was not a unique property of SaOS-2 cells, because primary human trabecular bone osteoblasts also produced significant amounts of bioactive IL-11 when stimulated with transforming growth factor-beta 1. These studies demonstrate that appropriately stimulated human osteoblasts and osteoblast-like cells are potent producers of IL-11 and suggest that osteoblast-derived IL-11 may be an important component of the cytokine network mediating osteoblast-osteoclast communication in normal and pathological bone remodeling.
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057.
J A
JA
Elias
W
W
Tang
M C
MC
Horowitz
D000293:Adolescent; D000328:Adult; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D000242:Cyclic AMP / Q000819:agonists; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D017370:Interleukin-11 / Q000096:biosynthesis*; D008875:Middle Aged; D010006:Osteoblasts / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein; D010954:Plasmacytoma / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011506:Proteins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D016207:Cytokines; D017370:Interleukin-11; C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D012333:RNA, Messenger; D000242:Cyclic AMP; D011493:Protein Kinase C