JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE 6 (1995) 762-767 Assessment of the role of cytokines in bone resorption in patients with total joint replacement N. AL SAFFAR”, P. A. REVELL, H. A. KHWAJA, W. BONFIELD Osteoarticular Research Group and Interdisciplinary Research Centre in Biomedical Materials, Department of Histopathology, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 ZPF, UK Periprosthetic osteolysis is known to be a consequence of a local chronic inflammatory reaction in the synovial tissue and the bone-implant interface membrane, and is mediated by macrophages (M$) and foreign body multinucleated giant cells (MNGC) in these tissues. Activated M4, produce major classes of cytokines which have been documented in the regulation of bone cell formation, function and activity. In rheumatoid arthritis, inflammatory mediators released by M$ participate significantly in articular tissue destruction. In this study we have analysed the production and tissue distribution of 4 cytokines in the interface membranes obtained from patients with osteolysis associated aseptic loosening and in rheumatoid synovium to determine their role in the functional transformation of effector cells in these two conditions. The production of IL-l, GM-CSF, IL-6 and TNF-a was assessed using immunohistochemistry on cryostat sections of the interface and the synovial tissues. IL-l and GM-CSF were detected in significantly high numbers of the inflammatory M+ in both RA and aseptic loosening. A specific pattern of expression was noted in the interface. IL-l production was sporadic throughout the sections, while GM-CSF was immunolocalized in a distinct subset of phagocytic macrophages on the implant side. IL-6 showed moderate expression in both conditions and was more widely produced at sites near the bone side in the interface. TNF-a expression was absent or reduced in the interface but was more abundant in RA synovial M$. The differential expression of cytokines indicates that bone lysis in these two pathological conditions is mediated by different mechanisms and regulated by different cytokines. 1. Introduction Cytokines include a large group of biologically active glycoproteins that mediate a number of cellular inter- actions and immune inflammatory responses. Data has also accumulated describing the potential of dif- ferent cytokines in the regulation of bone cell forma- tion, function and activity, particularly the bone resor- bing capacity of osteoclasts (OC), which is essential in bone remodelling [l]. The majority of these findings are based on in vitro and in vivo studies of the bone marrow microenvironment, the main source of bone cells [2]. It is now well established that bone-resor- bing OC are derived from haemopoietic mononuclear cells [3], while osteoblasts (OB), the bone-forming cells, originate from bone marrow stromal cells [4]. It is therefore apparent that the differentiation of haemo- poietic and bone cells is regulated by the same net- work of cytokines and growth factors produced within the bone marrow. Although a large number of these factors is produced by macrophages (M$), there is evidence that stromal cells, OB, T cells, fibroblasts and endothelial cells also synthesize high levels of these factors [ 11. Interleukin-1 (IL-l) and tumour necrosis factor (TNF-a) are the first known potent stimulators of bone resorption in vitro [S, 61 and in vivo [7]. They are often termed as OC activating factors. IL-l has also been shown to have an inhibitory effect on OB func- tion and bone collagen synthesis [8]. Reports also suggest that IL-l is partly responsible for post- menopausal osteoporosis [9], and increased hypercal- cemia in relation to various malignancies [lo]. In addition to its production by the M@/monocyte lineage, IL-6 has also been demonstrated in stromal cells, OB cell lines and non transformed human bone cells [ll]. It is the major cytokine responsible for the development of focal osteolytic lesions in multiple myeloma [12]. IL-6 acts as an autocrine/paracrine factor in Paget’s disease of bone [13]. Elevated levels of IL-6 produced by OC-like giant cells have been *To whom correspondence should be addressed 762 09514530 0 1995 Chapman & Hall