CYTOKINE AND HORMONAL-STIMULATION OF HUMAN OSTEOSARCOMA INTERLEUKIN-11 PRODUCTION

Osteoclast-mediated bone resorption plays a crucial role in osseous re modeling. Osteoblasts are important regulators of this activity, in pa rt through their ability to produce osteoclast-regulating soluble fact ors such as interleukin-6 (IL-6). IL-11 is a newly appreciated pleotro pic cytokine whose spectrum of biological activities overlaps with tha t of IL-6. As a result, we hypothesized that osteoblasts are an import ant skeletal source of this cytokine. To test this hypothesis, we char acterized the IL-11 production of unstimulated and stimulated SaOS-2 h uman osteosarcoma cells. Unstimulated cells produced modest amounts of IL-11. The osteotropic agents recombinant IL-1 (0.25-5 ng/ml), transf orming growth factor-beta 1 (0.1-10 ng/ml), PTH (10(-8)-10(-11) M), an d PTH-related peptide (10(-8)-10(-11) M) further increased SaOS-2 cell IL-11 protein production and messenger RNA accumulation. These stimul atory effects were dose and time dependent, and the IL-11 that was pro duced was bioactive, as demonstrated by its ability to stimulate the p roliferation of T10D plasmacytoma cells. The protein kinase-C activato r, 12-O-Tetra-decanoylphorbol 13-acetate, and a variety of cAMP agonis ts [forskolin, prostaglandin E(1), prostaglandin E(2), and (Bu)(2)AMP] also stimulated osteoblast IL-11 protein production and messenger RNA accumulation. In contrast, recombinant IL-4, recombinant interferon-g amma, and endotoxin did not stimulate SaOS-2 cells in a similar fashio n. Importantly, the ability to produce IL-11 was not a unique property of SaOS-2 cells, because primary human trabecular bone osteoblasts al so produced significant amounts of bioactive IL-11 when stimulated wit h transforming growth factor-beta 1. These studies demonstrate that ap propriately stimulated human osteoblasts and osteoblast-like cells are potent producers of IL-11 and suggest that osteoblast-derived IL-11 m ay be an important component of the cytokine network mediating osteobl ast-osteoclast communication in normal and pathological bone remodelin g.