Systemic and local cytokine kinetics after total hip replacement surgery.

BACKGROUND: Trauma induces local and subsequent systemic inflammatory reactions. Aberrant reactions can lead to a systemic inflammatory response syndrome, with a potentially lethal outcome. Our aim was to investigate the early local cytokine kinetic compared to systemic changes in a standardized surgical trauma. METHODS: In 7 patients with total hip replacement, drained blood samples and venous blood samples were taken 3 times within the first day after the operation. Interleukin (IL) release was assessed by a multiplex antibody bead kit and compared to pre-operative values. RESULTS: The major findings were significant increases in systemic levels of IL-6 and in local levels of IL-6, IL-8 and IL-1 receptor antagonist (IL-1Ra), and that the local levels of these cytokines were significantly higher than the systemic ones after surgery. Besides, there were only modest changes in local and systemic levels of tumour necrosis factor alpha, IL-1 beta, IL-2, IL-2Ra, IL-4, IL-5, IL-7, IL-10, IL-12, IL-13, IL-15 and IL-17. CONCLUSIONS: The acute sterile inflammation after major orthopaedic surgery is principally characterized by significantly increased local and systemic levels of IL-6 and significantly increased local levels of IL-8 and IL-1Ra. Furthermore, the concentrations are higher at the local site of injury. Hence, we conclude that systemic cytokine levels might not reflect local reactions.

Serotonin and fluoxetine modulate bone cell function in vitro.

Recent studies have proposed a role for serotonin and its transporter in regulation of bone cell function. In the present study, we examined the in vitro effects of serotonin and the serotonin transporter inhibitor fluoxetine "Prozac" on osteoblasts and osteoclasts. Human mononuclear cells were differentiated into osteoclasts in the presence of serotonin or fluoxetine. Both compounds affected the total number of differentiated osteoclasts as well as bone resorption in a bell-shaped manner. RT-PCR on the human osteoclasts demonstrated several serotonin receptors, the serotonin transporter, and the rate-limiting enzyme in serotonin synthesis, tryptophan hydroxylase 1 (Tph1). Tph1 expression was also found in murine osteoblasts and osteoclasts, indicating an ability to produce serotonin. In murine pre-osteoclasts (RAW264.7), serotonin as well as fluoxetine affected proliferation and NFkappaB activity in a biphasic manner. Proliferation of human mesenchymal stem cells (MSC) and primary osteoblasts (NHO), and 5-HT2A receptor expression was enhanced by serotonin. Fluoxetine stimulated proliferation of MSC and murine preosteoblasts (MC3T3-E1) in nM concentrations, microM concentrations were inhibitory. The effect of fluoxetine seemed direct, probably through 5-HT2 receptors. Serotonin-induced proliferation of MC3T3-E1 cells was inhibited by the PKC inhibitor (GF109203) and was also markedly reduced when antagonists of the serotonin receptors 5-HT2B/C or 5-HT2A/C were added. Serotonin increased osteoprotegerin (OPG) and decreased receptor activator of NF-kappaB ligand (RANKL) secretion from osteoblasts, suggesting a role in osteoblast-induced inhibition of osteoclast differentiation, whereas fluoxetine had the opposite effect. This study further describes possible mechanisms by which serotonin and the serotonin transporter can affect bone cell function.