Eine „Denkkultur der Nachhaltigkeit“ für Unternehmen

Nachhaltigkeit in Unternehmen braucht den  Menschen. Schulungsformate könnten einen Raum schaffen für kreatives Lösungssuchen,  gemeinsames Erleben und neue Denkgewohnheiten. Die Lust an individuellen Nachhaltigkeitsideen und deren Umsetzung am Arbeitsplatz könnte so zur Routine werden

Anti-NGF treatment worsens subchondral bone and cartilage measures while improving symptoms in floor-housed rabbits with osteoarthritis

Objective: Osteoarthritis (OA) is a common joint disorder often affecting the knee. It is characterized by alterations of various joint tissues including subchondral bone and by chronic pain. Anti-nerve growth factor (NGF) antibodies have demonstrated improvement in pain associated with OA in phase 3 clinical trials but have not been approved due to an increased risk of developing rapidly progressive OA. The aim of this study was to investigate effects of systemic anti-NGF-treatment on structure and symptoms in rabbits with surgically induced joint instability.Methods: This was elicited by anterior cruciate ligament transection and partial resection of the medial meniscus in right knee of 63 female rabbits, housed altogether in a 56 m2 floor husbandry. Rabbits received either 0.1, 1 or 3 mg/kg anti-NGF antibody intra-venously at weeks 1, 5 and 14 after surgery or vehicle. During in-life phase, static incapacitance tests were performed and joint diameter was measured. Following necropsy, gross morphological scoring and micro-computed tomography analysis of subchondral bone and cartilage were performed.Results: After surgery, rabbits unloaded operated joints, which was improved with 0.3 and 3 mg/kg anti-NGF compared to vehicle injection during the first half of the study. The diameter of operated knee joints increased over contralateral measures. This increase was bigger in anti-NGF treated rabbits beginning 2 weeks after the first IV injection and became dose-dependent and more pronounced with time. In the 3 mg/kg anti-NGF group, the bone volume fraction and trabecular thickness increased in the medio-femoral region of operated joints compared to contralateral and to vehicle-treated animals, while cartilage volume and to a lesser extent thickness decreased. Enlarged bony areas were found in right medio-femoral cartilage surfaces of animals receiving 1 and 3 mg/kg anti-NGF. Alterations of all structural parameters were particularly distinct in a subgroup of three rabbits, which also exhibited more prominent symptomatic improvement.Conclusion: This study showed that anti-NGF administration exerted negative impact on structure in destabilized joints of rabbits, while pain-induced unloading of joints was improved. Our findings open up the possibility to better understand the effects of systemic anti-NGF, particularly on subchondral bone, and thus the occurrence of rapidly progressive OA in patients

Translational strategies in drug development for knee osteoarthritis.

Osteoarthritis (OA) is a common disease worldwide with large unmet medical needs. To bring innovative treatments to OA patients, we at Merck have implemented a comprehensive strategy for drug candidate evaluation. We have a clear framework for decision-making in our preclinical pipeline, to design our clinical proof-of-concept trials for OA patients. We have qualified our strategy to define and refine dose and dosing regimen, for treatments administered either systemically or intra-articularly (IA). We do this through preclinical in vitro and in vivo studies, and by back-translating results from clinical studies in OA patients

Identification of novel SHOX target genes in the developing limb using a transgenic mouse model

Deficiency of the human short stature homeobox-containing gene (SHOX) has been identified in several disorders characterized by reduced height and skeletal anomalies such as Turner syndrome, Léri-Weill dyschondrosteosis and Langer mesomelic dysplasia as well as isolated short stature. SHOX acts as a transcription factor during limb development and is expressed in chondrocytes of the growth plates. Although highly conserved in vertebrates, rodents lack a SHOX orthologue. This offers the unique opportunity to analyze the effects of human SHOX expression in transgenic mice. We have generated a mouse expressing the human SHOXa cDNA under the control of a murine Col2a1 promoter and enhancer (Tg(Col2a1-SHOX)). SHOX and marker gene expression as well as skeletal phenotypes were characterized in two transgenic lines. No significant skeletal anomalies were found in transgenic compared to wildtype mice. Quantitative and in situ hybridization analyses revealed that Tg(Col2a1-SHOX), however, affected extracellular matrix gene expression during early limb development, suggesting a role for SHOX in growth plate assembly and extracellular matrix composition during long bone development. For instance, we could show that the connective tissue growth factor gene Ctgf, a gene involved in chondrogenic and angiogenic differentiation, is transcriptionally regulated by SHOX in transgenic mice. This finding was confirmed in human NHDF and U2OS cells and chicken micromass culture, demonstrating the value of the SHOX-transgenic mouse for the characterization of SHOX-dependent genes and pathways in early limb development

DataSheet1_Enlarged colony housing promotes linear progression of subchondral bone remodeling in joint instability rat models.docx

Objective: Osteoarthritis (OA) is a disease with high prevalence and an unmet medical need for disease modifying treatments. In rat models, OA-like subchondral bone and cartilage changes can be induced by instability surgery with different severity levels. Factors which determine structural changes additionally comprise the study duration and activity-impacted joint loading.Methods: A medial meniscal tear (MMT) or anterior cruciate ligament transection with partial meniscectomy (ACLT+pMx) was induced unilaterally in rats housed in a rat colony cage (RCC), allowing high activity levels including jumping and stair climbing. In parallel, ACLT+pMx rats were housed in Type IV cages. The time course of OA-related changes was investigated at 4, 8, 12, and 16 weeks after surgery by micro-CT, gait analysis and joint diameter measurements.Results: Gait disturbance was observed after 2 weeks and to a similar extend in all models. The increase in ipsilateral joint diameters peaked after 2 weeks and were more pronounced after ACLT+pMx compared to MMT-surgery, but independent of housing. Micro-CT analysis revealed that increases in osseous tibial width were most distinct after ACLT+pMx in RCC and progressed continuously until week sixteen. In contrast, osseous tibial width of ipsilateral joints in MMT RCC and ACLT+pMx Type IV groups did not increase further after week twelve. In contralateral joints, this parameter was not affected, regardless of the model or caging. However, a significant increase in bone volume fraction and trabecular thickness was observed over time in the femur and tibia of both ipsilateral and contralateral knees. Here, the medial tibial compartment of the operated joint was most affected and linear changes were most pronounced in the ACLT+pMx RCC group.Conclusion: Increased movement of animals in colony cages leads to robust structural changes in subchondral bone after surgically induced joint instability over time, while in regular Type IV housing maximal changes are reached in week twelve. The new insights into the differentiation of the models, particularly with respect to the linear progression of bone changes in ACLT+pMx in the RCC, may be useful for the design of chronic OA-studies within a longer lifespan and therefore supporting the development of novel therapies.</p

Increased bone formation in a rabbit long-bone defect model after single local and single systemic application of erythropoietin

Background and purpose — Delayed bone healing with non-union is a common problem. Further options to increase bone healing together with surgery are needed. We therefore evaluated a 1-dose single application of erythropoietin (EPO), applied either locally to the defect or systemically during surgery, in a critical-size rabbit long-bone defect. Material and methods — 19 New Zealand White rabbits received a 15-mm defect in the radius diaphysis. An absorbable gelatin sponge was soaked with saline (control group and systemic treatment group) or EPO (local treatment group) and implanted into the gap. The systemic treatment group received EPO subcutaneously. In vivo micro-CT analysis was performed 4, 8, and 12 weeks postoperatively. Vascularization was evaluated histologically. Results — Semiquantitative histomorphometric and radiological evaluation showed increased bone formation (2.3- to 2.5-fold) in both treatment groups after 12 weeks compared to the controls. Quantitative determination of bone volume and tissue volume showed superior bone healing after EPO treatment at all follow-up time points, with the highest values after 12 weeks in locally treated animals (3.0- to 3.4-fold). More vascularization was found in both EPO treatment groups. Interpretation — Initial single dosing with EPO was sufficient to increase bone healing substantially after 12 weeks of follow-up. Local application inside the defect was most effective, and it can be administered directly during surgery. Apart from effects on ossification, systemic and local EPO treatment leads to increased callus vascularization

Social landscape of the night parrot in western Queensland, Australia

The attitudes of the owners or managers of properties potentially supporting populations of night parrot (Pezoporus occidentalis) in western Queensland, Australia, were explored using interviews to understand whether they would be sympathetic to the species’ conservation. Eighteen interviews were carried out by a former member of the local grazing community and found a high level of support for conservation, especially if it did not unduly disrupt existing grazing management practices and there was compensation in the event property management needed to change. This included trying to limit burning and not overgrazing habitat in which the parrot might occur. It also included the cessation of wild dog baiting, which is conducted to reduce calf losses, although concern about wild dogs was deeply entrenched. While some graziers were indifferent, none were openly antagonistic to parrot conservation that might involve their property. The results suggest that collaborative management with local graziers can contribute substantially to conservation of the night parrot in the region and any fears that graziers might be antagonistic to night parrot conservation are ill-founded

Melanocortin 1 receptor-signaling deficiency results in an articular cartilage phenotype and accelerates pathogenesis of surgically induced murine osteoarthritis

Proopiomelanocortin-derived peptides exert pleiotropic effects via binding to melanocortin receptors (MCR). MCR-subtypes have been detected in cartilage and bone and mediate an increasing number of effects in diathrodial joints. This study aims to determine the role of MC1-receptors (MC1) in joint physiology and pathogenesis of osteoarthritis (OA) using MC1-signaling deficient mice (Mc1re/e). OA was surgically induced in Mc1re/e and wild-type (WT) mice by transection of the medial meniscotibial ligament. Histomorphometry of Safranin O stained articular cartilage was performed with non-operated controls (11 weeks and 6 months) and 4/8 weeks past surgery. µCT–analysis for assessing epiphyseal bone architecture was performed as a longitudinal study at 4/8 weeks after OA-induction. Collagen II, ICAM-1 and MC1 expression was analysed by immunohistochemistry. Mc1re/e mice display less Safranin O and collagen II stained articular cartilage area compared to WT prior to OA-induction without signs of spontaneous cartilage surface erosion. This MC1-signaling deficiency related cartilage phenotype persisted in 6 month animals. At 4/8 weeks after OA-induction cartilage erosions were increased in Mc1re/e knees paralleled by weaker collagen II staining. Prior to OA-induction, Mc1re/e mice do not differ from WT with respect to bone parameters. During OA, Mc1re/e mice developed more osteophytes and had higher epiphyseal bone density and mass. Trabecular thickness was increased while concomitantly trabecular separation was decreased in Mc1re/e mice. Numbers of ICAM-positive chondrocytes were equal in non-operated 11 weeks Mc1re/e and WT whereas number of positive chondrocytes decreased during OA-progression. Unchallenged Mc1re/e mice display smaller articular cartilage covered area without OA-related surface erosions indicating that MC1-signaling is critical for proper cartilage matrix integrity and formation. When challenged with OA, Mc1re/e mice develop a more severe OA-pathology. Our data suggest that MC1-signaling protects against cartilage degradation and subchondral bone sclerosis in OA indicating a beneficial role of the POMC system in joint pathophysiology

R399E, A Mutated Form of Growth and Differentiation Factor 5, for Disease Modification of Osteoarthritis.

Funder: Merck KGaA; Id: http://dx.doi.org/10.13039/100009945OBJECTIVE: To preclinically characterize a mutant form of growth and differentiation factor 5, R399E, with reduced osteogenic properties as a potential disease-modifying osteoarthritis (OA) drug. METHODS: Cartilage, synovium, and meniscus samples from patients with OA were used to evaluate anabolic and antiinflammatory properties of R399E. In the rabbit joint instability model, 65 rabbits underwent transection of the anterior cruciate ligament plus partial meniscectomy. Three intraarticular (IA) R399E doses were administered biweekly 6 times, and static incapacitance was determined to assess joint pain. OA was evaluated 13 weeks after surgery. In sheep, medial meniscus transection was performed to induce OA, dynamic weight bearing was measured in-life, and OA was assessed after 13 weeks. RESULTS: Intermittent exposure to R399E (1 week per month) was sufficient to induce cell proliferation and release of anabolic markers in 3-dimensional chondrocyte cultures. R399E also inhibited the release of interleukin-1β (IL-1β), IL-6, and prostaglandin E2 from cartilage with synovium, meniscal cell, and synoviocyte cultures. In rabbits, the mean difference (95% confidence interval [95% CI]) in weight bearing for R399E compared to vehicle was -5.8 (95% confidence interval [95% CI] -9.54, -2.15), -7.2 (95% CI -10.93, -3.54), and -7.7 (95% CI -11.49, -3.84) for the 0.6, 6, and 60 μg doses, respectively, 6 hours after the first IA injection, and was statistically significant through the entire study for all doses. Cartilage surface structure improved with the 6-μg dose. Structural and symptomatic improvement with the same dose was confirmed in the sheep model of OA. CONCLUSION: R399E influences several pathologic processes contributing to OA, highlighting its potential as a disease-modifying therapy