We have investigated whether the particle-stimulated release of inflammatory cytokines from human primary macrophages in vitro was dependent upon the type of bone cement used. Particles of clinically relevant size were produced from Palacos R without radio-opacifier, Palacos R with BaSO. 4. , Palacos R with ZrO. 2. and from CMW3 which contains BaSO. 4. All four preparations produced significantly greater release of tumour necrosis factor alpha, interleukin-6 and interleukin-1 beta than a negative control but there were no significant differences between them. The differences in the ability to stimulate bone resorption and in clinical performance between proprietary bone cements previously recorded are not explained by the release of the cytokines most commonly implicated in osteolysis

The interactions between the different cell types in periprosthetic tissue are still unclear. We used a non-contact coculture model to investigate the effects of polymethylmethacrylate (PMMA) particles and human macrophage-derived soluble mediators on fibroblast activation. Macrophages were either exposed or not exposed to phagocytosable PMMA particles, but fibroblasts were not. Increasing numbers of macrophages were tested in cocultures in which the fibroblast cell number was held constant and cultures of macrophages alone were used for comparison of cytokine release. We used the release of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), lysosomal enzyme and metalloproteinase activity to assess the cultivation of macrophages and fibroblasts. In cocultures, IL-6 release was increased 100-fold for both unchallenged and particle-challenged cultures when compared with macrophage cultures alone. Furthermore, particle-challenged cocultures had threefold higher IL-6 levels than unchallenged cocultures. Release of TNF-α was similar in cocultures and in macrophage cultures. IL-1β release in cocultures was independent of the macrophage-fibroblast ratio. Lysosomal enzyme activity and metalloproteinase activity were increased in cocultures. Our data show that macrophages and fibroblasts in coculture significantly increase the release of IL-6 and to a less degree other inflammatory mediators; particle exposure accentuates this effect. This suggests that macrophage accumulation in fibrous tissue may lead to elevated IL-6 levels that are much higher than those caused by particle activation of macrophages alone. This macrophage-fibroblast interaction represents a novel concept for the initiation and maintenance of the inflammatory process in periprosthetic membranes

The role of inflammatory cells and their products in tendinopathy is not completely understood. Pro-inflammatory cytokines are upregulated after oxidative and other forms of stress. Based on observations that increased cytokine expression has been demonstrated in cyclically-loaded tendon cells we hypothesised that because of their role in oxidative stress and apoptosis, pro-inflammatory cytokines may be present in rodent and human models of tendinopathy. A rat supraspinatus tendinopathy model produced by running overuse was investigated at the genetic level by custom micro-arrays. Additionally, samples of torn supraspinatus tendon and matched intact subscapularis tendon were collected from patients undergoing arthroscopic shoulder surgery for rotator-cuff tears and control samples of subscapularis tendon from ten patients with normal rotator cuffs undergoing arthroscopic stabilisation of the shoulder were also obtained. These were all evaluated using semiquantitative reverse transcription polymerase chain-reaction and immunohistochemistry.

We identified significant upregulation of pro-inflammatory cytokines and apoptotic genes in the rodent model (p = 0.005). We further confirmed significantly increased levels of cytokine and apoptotic genes in human supraspinatus and subscapularis tendon harvested from patients with rotator cuff tears (p = 0.0008).

These findings suggest that pro-inflammatory cytokines may play a role in tendinopathy and may provide a target for preventing tendinopathies.