There is increasing evidence that IL-6 may function as a bone-active cytokine. IL-1, which itself exerts potent effects on bone cells, is a potent stimulator of IL-6 release in several connective tissue cell types. Furthermore, these cytokines exhibit strikingly similar biological activities in other tissues. It is therefore possible that IL-6 may mediate the effects of IL-1 in bone. In this thesis, the synthesis and factors regulating the production of IL-6 protein and mRNA by human osteoblast-like cells was investigated. In addition, the effects of IL- 6 on human osteoblast-like cell function was determined. A rat osteosarcoma cell line was used as a comparative osteoblast-like model.

The cytokines IL-1 and TNF, but not the osteotropic hormones PTH and 1,25(OH)₂D₃, induced the synthesis of IL-6 mRNA and protein from human osteoblast-like cells whereas PTH was the most potent stimulator of IL-6 protein release in the rat osteosarcoma cells. Despite the high levels of production of IL-6 , this cytokine exerted no effect on various osteoblast cell activities including cell proliferation, cytokine and prostaglandin release and expression of differentiated phenotype.

Although human osteoblast-like cells apparently lacked responsiveness to IL-6 , Northern and dot blot analysis of IL- 6 receptor mRNA showed that the transcript was constitutively expressed but not modulated by any of the factors above. Lack of effects of IL-6 on osteoblasts could be due to the expression of non-functional receptors.

To provide a clearer understanding of the possible role of IL-6 in bone physiology in vivo, IL-6 mRNA production in actively remodelling human bone tissue was studied by in situ hybridisation. Expression of this cytokine was observed in many cell types including cells with the appearance of newly formed osteoblasts as well as osteoblasts and osteoclasts adjacent to the bone surface and marrow stromal cells. The demonstration of the presence of IL-6 in bone sections shows that IL-6 production by osteoblasts in culture is not artifactual. Further in situ hybridisation studies are required to co-localise IL-6 mRNA with osteoblast and osteoclast markers in order to gain more information about the role of this cytokine in vivo. That several cell types are apparently capable of synthesising IL-6 in the bone microenvironment provides strong evidence that IL-6 may co-ordinate certain cellular events within bone such as hematopoiesis. However, the failure of IL-6 to affect osteoblast activity in vitro may discount a direct role in bone formation. The importance of osteoblast-derived IL-6 and its involvement in normal bone remodelling remains to be elucidated.