Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain is the predominant clinical feature, yet therapy is ineffective for many patients. While there are considerable insights into the mechanisms underlying tissue remodelling, there is poor understanding of the link between disease pathology and pain. This is in part owing to the lack of animal models that combine both osteoarthritic tissue remodelling and pain. Here, we provide an analysis of pain related behaviours in two models of OA in the rat: partial medial meniscectomy and iodoacetate injection. Histological studies demonstrated that in both models, progressive osteoarthritic joint pathology developed over the course of the next 28 days. In the ipsilateral hind limb in both models, changes in the percentage bodyweight borne were small, whereas marked mechanical hyperalgesia and tactile allodynia were seen. The responses in the iodoacetate treated animals were generally more robust, and these animals were tested for pharmacological reversal of pain related behaviour. Morphine was able to attenuate hyperalgesia 3, 14 and 28 days after OA induction, and reversed allodynia at days 14 and 28, providing evidence that this behaviour was pain related. Diclofenac and paracetamol were effective 3 days after arthritic induction only, coinciding with a measurable swelling of the knee. Gabapentin varied in its ability to reverse both hyperalgesia and allodynia. The iodoacetate model provides a basis for studies on the mechanisms of pain in OA, and for development of novel therapeutic analgesics.

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Our results indicate a role for MT1-MMP not only in the matrix degradation by fibroblasts, but also in osteoclast-mediated bone resorption in RA. Given the ability of MT1-MMP to activate MMP-2 and MMP-13, the findings also point to a cooperation between fibroblasts and macrophages in degrading cartilage and bone. While MT3-MMP is also intensely expressed in RA synovium, MT2- and MT4-MMP appear not to be involved in rheumatoid joint destruction.

O&ective. To identw differences in levels of insulinlike growth factor (IGF) and IGF binding proteins (IGFBPs) between 30 patients with arthritis (14 with rheumatoid arthritis [RA], 16 with osteoarthritis [OA]) and 11 normal control subjects. IGF and IGFBP levels were correlated to the disease activity marker C-reactive protein (CRP) to determine whether they were disease related. We also examined the degree of proteolytic modification of the IGFBPs.Methods. Radioimmunoassays were used for measuring IGF and IGFBP-3 levels; CRP was measured by enzyme-linked immunosorbent assay. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western blotting, chemiluminescence, and autoradiography were used for visualizing binding proteins.Results. There was a significant increase in synovial fluid levels of both IGF-1 and IGFBP-3 in both RA and OA. This resulted in an elevated IGFBP-3 to IGF molar ratio of 1.49 in the OA group and 1.47 in the RA group, compared with 0.86 in the normal control group (P = 0.0002 for both). A significantly lower degree of IGFBP-3 proteolysis was also seen in the synovial fluids from the patients compared with the controls. There were significant correlations between the CRP level and levels of IGF-1, IGF-2, and IGFBP-3 in the RA patients (r = 0.62-0.898, P = 0.04-0.0007).Conclusion. There was significant local disruption of the IGF system in patients with arthritis. This may result in a lower amount of IGF that is able to bind to IGF receptors in the arthritic joint. Levels of IGF-1, IGF-2, and IGFBP-3 all correlated with the CRP level in Supported by the Throckmorton Scholarship, University of Bristol.

Objective. Epidemiologic studies have suggested that estrogen replacement therapy may lower the risk of osteoarthritis in women, but the mechanism of this effect is unknown. Since estrogen acts in other tissues in part through regulation of the insulin-like growth factor (IGF) system as well as cytokines including interleukin-6 (IL-6), we determined whether estrogen replacement regulates the levels of these factors in synovial fluid (SF).Methods. Levels of IGF-1, IGF-2, IGF binding proteins (IGFBP) 1-3, and IL-6 were measured in SF samples obtained from 67 female adult cynomolgus monkeys that had been ovariectomized and treated for 30 months in 1 of 3 groups. Group 1 (n ‫؍‬ 24) had no estrogen replacement (control), group 2 (n ‫؍‬ 22) received estrogen (Premarin) at the human equivalent of 0.625 mg/day, and group 3 (n ‫؍‬ 21) received estrogen at the same dose as group 2, plus progesterone (Provera) at the equivalent of 2.5 mg/day.Results. Compared with controls, estrogentreated monkeys had 2-fold higher SF levels of IGF-1 (P < 0.001), 1.7-fold higher IGF-2 (P < 0.006), 5.9-fold higher IGFBP-1 (P < 0.02), and 2.5-fold higher IGFBP-3 (P < 0.001). Estrogen plus progesteronetreated monkeys had SF levels of IGF-1, IGF-2, IGFBP-1, and IGFBP-3 that were intermediate between the levels in the control and estrogen groups, except that the level of IGFBP-3 was significantly greater than that in the control group (P < 0.001). SF levels of IGFBP-2 and IL-6 did not differ by treatment group. Treatment group did not affect the serum levels of IGF-1 and IL-6, but IGF-2 and IGFBP-3 were increased by 1.6-and 1.8-fold, respectively, in the estrogen group (P < 0.001). There was no correlation between changes in serum and SF levels of IGF components, except for a weak correlation for IGFBP-3 levels from control (r ‫؍‬ 0.464, P ‫؍‬ 0.04) and estrogen-treated (r ‫؍‬ 0.577, P ‫؍‬ 0.008) animals.Conclusion. This study demonstrates a significant effect of estrogen replacement on IGF system components in synovial fluid, of which at least some are distinct from any systemic changes observed. The results indicate a potential stimulatory effect of estrogen on joint tissues in vivo.The prevalence of osteoarthritis (OA) increases with age in both men and women, but, when compared with men, women have a higher prevalence of OA past the age of 50. Women have been shown to have a 1.7 times higher rate of incident knee OA compared with men (1), and the sex differential increases even further as older age groups are considered, with an up to 4-fold higher prevalence of knee OA in 70-to 96-year-old women compared with men (2). Estrogen deficiency has been implicated as a contributing factor in other conditions such as heart disease, osteoporosis, and gout, in which the risk in women increases significantly after menopause. It is possible that a higher prevalence of OA in older women could also be related, at least in part, to postmenopausal estrogen loss.In support of a role for estrogen loss in the development of OA, several recent human epidemiol...