Background: Periprosthetic osteolysis precipitates aseptic component loosening, increases periprosthetic fracture risk and through massive bone loss, complicates revision surgery. Its pathogenesis is based upon the generation of wear debris particles which trigger synovial macrophage activation. Statins, inhibitors of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-Co-A) reductase, have revolutionised the treatment of hypercholesterolaemia and cardiovascular disease. The antiinflammatory properties of HMG-CoA reductase inhihitors or the statin family are well recognised. We investigated the effects of ceriv-astatin in attenuating the activation of human macrophages by polymethylmethacrylate (PMMA) particles. Methods: Polymethylmethacrylate-particle-stimulated human macrophages were cultured in vitro with cerivastatin at 75 and 150micromols/litre. TNF- alpha (tumour necrosis factor alpha) and MCP-1 (monocyte chemotactic protein) expression were determined using ELISA. UO126, a Raf/MEK/ERK intracellular transduction pathway inhibitor, was utilised to identify the mitogen activated protein kinase (MAP- Kinase) pathway involved and western blotting was used to demonstrate the effect of cerivastatin on this pathway. Results Human monocyte/macrophage cultures were activated by PMMA particles evidenced by TNF- alpha and MCP-1 expression(p< 0.05). This activation was consistently attenuated by cerivastatin therapy. Similarily, PMMA activation was attenuated by the Raf/MEK/ERK inhibitor, UO126. Western blotting confirmed Raf/MEK/ERK down-regulation by cerivastatin, establishing a mechanism for its anti-inflammatory effects. Conclusion We have demonstrated in vitro, that statins can abrogate particle induced inflammatory responses in a dose dependent manner and this is mediated intra-cellularily through its effect on the Raf/MEK/ERK transduction pathway. We propose that by attenuating this inflammatory response, the associated subsequent osteoclast activation and osteolysis is attenuated. Statins therefore may have role in promoting implant longevity

Introduction. Matrix metalloproteinases (MMP) play a key role in cartilage degradation in osteoarthritis. Statins are a potential suppressor of MMPs. The aim of this research was to assess the efficacy of Pravastatin in suppressing MMP gene and protein expression in an in vitro model. Methods. We stimulated normal human chondrocytes with IL-1b for 6 hours to induce MMP expression and then treated with Pravastatin (1, 5 & 10 mM) for a further 18 hours. Cells stimulated with IL-1b but not treated with Pravastatin served as controls. Real-time PCR was used to assess expression of MMP-3 and MMP-9 mRNA. MMP enzyme activity was assessed using a fluorescent MMP-specific substrate. Staistical analysis was performed using ANOVA. Results. MMP-3 and -9 mRNA expression was reduced at all concentrations tested with a statistically significant trends in reduction (p=0.002 and < 0.001 respectively). Analaysis of culture supernatants revealed that Pravastatin treatment led to a reduction in total MMP activity but not to a statistically significant degree (p=0.07). Conclusion. We conclude that treatment with Pravastatin of stimulated human chondrocytes leads to a down regulation of selected MMP genes and a reduction in MMP enzyme activity. Our results are further evidence that statins may have a role to play in the treatment of osteoarthritis and other disorders of cartilage degradation

Background: Aseptic loosening remains the most common cause of failure of total hip arthroplasty. Its pathogenesis is based upon the generation of wear debris particles which trigger synovial macrophage activation. Statins, inhibitors of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-Co-A) reductase, have revolutionised the treatment of hypercholesterolaemia. More recently statins have been shown to have potent anti inflammatory effects. We investigated the effects of cerivastatin in attenuating the activation of human macrophages by polymethylmethacrylate (PMMA) particles. Methods: Polymethylmethacrylate-particle-stimulated human macrophages were cultured in vitro with cerivastatin at 75 and 150... mols/litre. TNF-α (tumour necrosis factor alpha) and MCP-1 (monocyte chemotactic protein) expression were determined using ELISA. An ERK1/2 inhibitor, UO126 was utilised to identify the mitogen activated protein kinase (MAP-Kinase) pathway involved and western blotting was used to demonstrate the effect of Cerivastatin on this pathway. Results PMMA-stimulated TNF-α and MCP-1 expression was consistently attenuated by cerivastatin therapy. PMMA activation was attenuated by the ERK1/2 inhibitor, UO126. Western blotting confirmed ERK downregulation by cerivastatin, establishing a mechanism for its anti-inflammatory effects. Conclusion: We have demonstrated the beneficial effects of statins in suppressing particle mediated activation of macrophages and the potential to prevent or treat periprosthetic osteolysis

Objectives

The primary purpose of this meta-analysis was to determine whether statin usage could reduce the risk of glucocorticoid-related osteonecrosis in animal models.

Background & Objectives: Statins have been shown to stimulate bone formation in vivo and in vitro in rodent models1 generating interest in the possibility that they may be useful therapeutic agents for osteoporosis. The major clinical consequence of osteoporosis are fractures that occur and although there is no firm evidence, there is a perceived associated delay in fracture repair. We examined the influence of atorvastatin on fracture repair in an ovariectomised rat fracture model. Methods: 126 Sprague-Dawley rats had an ovariectomy (OVX) at three months and a femoral fracture (F) at six months. The fracture consisted of an open osteotomy held with an external fixator. All animals were randomly assigned into groups 1. OVX+F and early atorvastatin; 2. OVX+F and late atorvastatin; 3. OVX+F. Atorvas-tatin (5mg/kg) was given daily by oral gavage for three months in-group 1 between OVX and fracture and from time of fracture to sacrifice in-group 2. Outcome measures were histology, peripheral quantitative computed tomography (pQCT), biomechanical strength testing (BST) and digital radiography. Digital radiographs were taken at time of OVX, fracture (confirming satisfactory reduction) and sacrifice from which relative bone density (BMD) measurements were calculated. Results: Non-statin treated animals moved significantly more in 4 days post-fracture (p=0.015), had signifi-cantly more relative (p=0.037) and total BMD (distal femur) than statin treated (p=0.040, early and p=0.036, late treatment). Total BMD at the fracture site was also significantly greater in the OVX+F than the late statin group (p=0.047) while in the adjacent site of the con-tralateral limb, the early statin group had significantly more (p=0.018) than the late statin group. However no differences were found between the early statin and OVX+F groups. Histologically, the rate of repair increased significantly in early statin (p=0.013) and OVX+F (p=0.011) groups. BST data showed no signifi-cant difference in stiffness at six or eight weeks. Conclusion: Fractures healed in all three groups. Statins did not prevent OVX induced bone loss. Initial evidence suggests that early statin treatment may have a positive effect on early fracture, as shown by x-ray analysis and histology, however this effect was lost by week 8. Overall the evidence suggests that atorvastatin may have impaired fracture repair, particularly with late administration (relative BMD and pQCT results)

Simvastatin is a 3-Hydroxy-3-methylglutaryl Co-enzyme inhibitor, widely used to reduce lipid levels. Recent studies have demonstrated pleiotropic beneficial effects the skeleton. We aim to demonstrate the effect of Simvastatin on the osteogenic differentiation and proliferation of murine embryonic stem cells. Tg2a cells were cultured in maintenance medium until confluence and passaged twice into tissue culture flasks. They were then seeded into 6 well and 24 well plates at a density of 10.000 cells/cm2 and cultured for 3 days in maintenance medium mixed at 1:1 with HepG2 conditioned medium. The culture then continued using osteogenic medium with different concentrations of simvastatin for another 16 days. Measurements included Alizarin Red quantification for calcified matrix, ALP assay, RT-PCR for genes expressed during osteogenic differentiation (osteocalcin, Runx2, osterix, Col1a1). Simvastatin has dose dependent effect on mineralized matrix formation. Alizarin Red quantification assays demonstrated that simvastatin (all dose groups) induced a statistically significant increase in calcified matrix formation on day 11 (P< 0.05) and 16 (P< 0.01) compared to the control group. ALP activity was significantly higher on day 8 in the groups that had a simvastatin concentration of 1nM, 10nM and 100nM (P< 0.05). RT-PCR has demonstrated that simvastatin caused increased expression of all genes measured on differentiation. Statins can induce bone formation when combined with embryonic stem cells

Introduction: Our previous study found that glucocorticoids shifted the properties of osteogenesis to adipogenesis in murine marrow stem cells. These effects may be one of the important mechanisms in the pathogenesis of osteonecrosis. Statins prevented these steroid effects. In this study, we investigated the effects of dexamethasone and lovastatin on the expressions of bone morphogenetic protein-2 (BMP2) in the bone marrow stroma cells cultured from osteonecrotic patients. Materials and Methods: Bone marrow fluid aspiration from iliac crest was performed in osteonecrosis (ON) and non-ON patients after surgical treatment for their hip disorder. The mean age of the patients was 59 years in the ON group and 63 years in the non-ON group. Nucleated stroma cells were isolated from bone marrow fluid by percol separation. The third passage cultures were used for experiments. Drug treatments for cultures included dexamethasone (10. −7. M), lovastatin (10. −6. M), and dexamethasone plus lovastatin for 4 days. BMP-2 mRNA expression was evaluated by RT-PCR. Different responses to drugs between the ON group and the non-ON group were compared. Results: Bone marrow stroma cells of ON patients were found to be more susceptible to the suppressive effect of dexamethasone on BMP2 expression. Discussion: Lovastatin stimulated the osteogenesis and reversed the steroid suppressive effect in bone marrow stroma cells in non-ON cases. However, this reverse effect was found to be mild in ON cases

Aims

Deciphering the genetic relationships between major depressive disorder (MDD) and osteoarthritis (OA) may facilitate an understanding of their biological mechanisms, as well as inform more effective treatment regimens. We aim to investigate the mechanisms underlying relationships between MDD and OA in the context of common genetic variations.