Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N ¼ 9). Exposure to ZOL at low micromolar concentrations induced a dose-and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy. ß
Purpose Limited data exist regarding the long-term results or risk factors for failure after two-stage reimplantation for periprosthetic knee infection. The purpose of this retrospective review was to investigate infection-free implant survival and identify variables associated with reinfection after this procedure. Furthermore, a staging system was evaluated as a possible prognostic tool for patients undergoing two-stage reimplantation of infected total knee arthroplasty (TKA). Methods In this level II, retrospective prognostic study, 368 patients with infected TKA treated with a two-stage revision protocol at our institution between 1998 and 2006 were reviewed. Patients who developed recurrent infection and an equal number of patients randomly selected for the control group were analysed for risk factors associated with treatment failure. Results At the most recent follow-up, 58 (15.8%) patients had developed reinfection after the two-stage reimplantation. The median time to reinfection was 1,303 days (3.6 years), with follow-up time ranging from six to 2,853 days (7.8 years). The strongest positive predictors of treatment failure included chronic lymphoedema [hazard ratio (HR)=2.28, 95% confidence interval (CI) 1.16-4.48; p=0.02),and revision between resection and definitive reimplantation (HR=2.13, 95% CI 1.20-3.79; p=0.01, whereas patients treated with intravenously administered Cefazolin had a significant reduction in recurrent infection rate (HR=0.48, 95% CI 0.25-0.90; p=0.02). Conclusions Our findings should be of help in counselling patients regarding their prognosis when faced with twostage exchange for infected TKA and provide a basis for future comparisons.
With its ease of use and rapid results after approximately ten minutes, Synovasure may be a useful adjunct in the diagnosis of PJI. Cite this article: Bone Joint J 2017;99-B:66-72.
Inflammatory chemo- and cytokines and matrix-degrading proteases underlie the progression of osteoarthritis (OA). Aiming to define upstream regulators for these disease markers, we pursued initial evidence for an upregulation of members of the adhesion/growth-regulatory galectin family. Immunohistochemical localization of galectin-3 (Gal-3) in sections of human cartilage with increasing levels of degeneration revealed a linear correlation reaching a chondrocyte positivity of 60%. Presence in situ was cytoplasmic, the lectin was secreted from OA chondrocytes in culture and binding of Gal-3 yielded lactose-inhibitable surface staining. Exposure of cells to the lectin led to enhanced gene expression and secretion of functional disease markers. Genome-wide transcriptomic analysis broadened this result to reveal a pro-degradative/inflammatory gene signature under the control of NF-κB. Fittingly, targeting this route of activation by inhibitors impaired the unfavourable response to Gal-3 binding, as also seen by shortening the lectin’s collagen-like repeat region. Gal-3’s activation profile overlaps with that of homodimeric galectin-1 (Gal-1) and also has distinctive (supplementing) features. Tested at subsaturating concentrations in a mixture, we found cooperation between the two galectins, apparently able to team up to promote OA pathogenesis. In summary, our results suggest that a network of endogenous lectins is relevant for initiating this process cascade.
The reading of glycan-encoded signals by tissue lectins is considered a major route of the flow of biological information in many (patho)physiological processes. The arising challenge for current research is to proceed from work on a distinct protein to family-wide testing of lectin function. Having previously identified homodimeric galectin-1 and chimera-type galectin-3 as molecular switches in osteoarthritis progression, we here provide proof-of-principle evidence for an intra-network cooperation of galectins with three types of modular architecture. We show that the presence of tandem-repeat-type galectin-8 significantly correlated with cartilage degeneration and that it is secreted by osteoarthritic chondrocytes. Glycan-inhibitable surface binding of galectin-8 to these cells increased gene transcription and the secretion of functional disease markers. The natural variant galectin-8 (F19Y) was less active than the prevalent form. Genome-wide array analysis revealed induction of a pro-degradative/inflammatory gene signature, largely under control of NF-κB signaling. This signature overlapped with respective gene-expression patterns elicited by galectins-1 and -3, but also presented supplementary features. Functional assays with mixtures of galectins that mimic the pathophysiological status unveiled cooperation between the three galectins. Our findings shape the novel concept to consider individual galectins as part of a so far not realized teamwork in osteoarthritis pathogenesis, with relevance beyond this disease.Electronic supplementary materialThe online version of this article (10.1007/s00018-018-2856-2) contains supplementary material, which is available to authorized users.
PurposeTo prevent early failure it is necessary to evaluate modern TKA system for possible shortcomings during implantation. The aim of this study was to evaluate the radiographic outcome and short-term survival of a modern cemented primary TKA system compared to its predecessor.MethodsThe authors reviewed 529 primary cemented TKAs [276 Attune (ATT) and 253 PFC Sigma (PFC)], which were implanted between 2014 and 2017 concerning the radiographic outcome and short-term survival. Radiographs were taken before discharge, 6 weeks, 6 months and 12 months postoperatively. Radiographic analysis was performed by two independent assessors using the Modern Knee Society Radiographic Evaluation System.ResultsThe incidence of radiolucent lines was significantly higher in the ATT group compared with the PFC group 12 months postoperatively (35.1%; n = 97 TKAs vs. 7.5%; n = 19 TKAs; p < 0.001). Survival analysis could not show any differences in revision-free survival or revision rate.ConclusionThe modern primary TKA system shows an increased number of radiolucent lines, especially on the tibial component in this short-term analysis and may mostly be due to technique-related issues. Patients with those radiolucent lines even though they show no clinical evidence for loosening should be closely monitored at regular intervals. These findings are of vital clinical importance because surgeons should be aware of particular challenges in preparation and cementing technique once they are using this TKA-system.Level of evidenceRetrospective cohort study, Level III.Electronic supplementary materialThe online version of this article (10.1007/s00167-018-5130-0) contains supplementary material, which is available to authorized users.
BackgroundEnhanced signalling via the epidermal growth factor receptor (EGFR) is a hallmark of multiple human carcinomas. However, in recent years data have accumulated that EGFR might also be hyperactivated in human sarcomas. Aim of this study was to investigate the influence of EGFR inhibition on cell viability and its interaction with chemotherapy response in osteosarcoma cell lines.MethodsWe have investigated a panel of human osteosarcoma cell lines regarding EGFR expression and downstream signalling. To test its potential applicability as therapeutic target, inhibition of EGFR by gefitinib was combined with osteosarcoma chemotherapeutics and cell viability, migration, and cell death assays were performed.ResultsOsteosarcoma cells expressed distinctly differing levels of functional EGFR reaching in some cases high amounts. Functionality of EGFR in osteosarcoma cells was proven by EGF-mediated activation of both MAPK and PI3K/AKT pathway (determined by phosphorylation of ERK1/2, AKT, S6, and GSK3β). The EGFR-specific inhibitor gefitinib blocked EGF-mediated downstream signal activation. At standard in vitro culture conditions, clinically achievable gefitinib doses demonstrated only limited cytotoxic activity, however, significantly reduced long-term colony formation and cell migration. In contrast, under serum-starvation conditions active gefitinib doses were distinctly reduced while EGF promoted starvation survival. Importantly, gefitinib significantly supported the anti-osteosarcoma activities of doxorubicin and methotrexate regarding cell survival and migratory potential.ConclusionOur data suggest that EGFR is not a major driver for osteosarcoma cell growth but contributes to starvation- and chemotherapy-induced stress survival. Consequently, combination approaches including EGFR inhibitors should be evaluated for treatment of high-grade osteosarcoma patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0251-5) contains supplementary material, which is available to authorized users.
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