Introduction

Periprosthetic osteolysis resulting in aseptic loosening is a leading cause for total hip arthroplasty (THA) failure. Individuals vary in their susceptibility to osteolysis, and it is thought that heritable factors contribute to this variation. We conducted two genome-wide association studies to identify genetic risk loci associated with osteolysis and genetic risk loci associated with time to prosthesis failure due to osteolysis.

Aims

The aim of this study was to screen the entire genome for genetic markers associated with risk for anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injury.

This is the largest reported natural history study of frozen shoulder. 500 patients were identified from a specialist shoulder clinic register with a diagnosis of frozen shoulder based on Codman’s criteria. 273 patients with primary frozen shoulder replied to a detailed postal questionnaire regarding their condition. Mean follow up from symptom onset was 52 months (range 12–240months), with 89% of shoulders followed up for a minimum of 3 years. A positive family history was identified in 20% (n=45) of 1st degree relatives. The relative risk to siblings compared with a control population was 4:1. Patients with mild to moderate symptoms recovered more quickly than those with severe or unbearable symptoms. The mean age of onset was 53 years (range27–85yrs). The female to male ratio was 1.6:1. The condition was bilateral in 20%, with no incidence of ipsilateral recurrence. 22% of patients reported a history of minor trauma to the upper limb prior to the onset of symptoms. 16% were diabetic and 4% reported a history of Dupuytren’s contracture. Right and left arms were affected equally with no relationship to hand dominance. 61% reported slow, and 39% reported sudden onset of symptoms. Generally pain and stiffness improved with time but at 3 and 4 years after onset 13% and 9% respectively still had symptoms.

Frozen shoulder affects people mainly in their 6th decade. Genetic factors play an important role in the aetiology. The natural history is for improvement with time, with the less severe symptoms at onset improving most quickly. 9% of patients were still symptomatic at 4 year follow up.

Introduction

From the many human studies that attempt to identify genes for adolescent idiopathic scoliosis (AIS), the view emerging is that AIS is a complex genetic disorder with many predisposing genes exhibiting complex phenotypes through environmental interactions. Although advancements in genomic technology are transforming how we undertake genetic and genomic studies, only some success has been reached in deciphering complex diseases such as AIS. Moreover, the present challenge in AIS research is to understand the causative and correlative effects of discovered genetic perturbations. An important limitation to such investigations has been the absence of a method that can easily stratify patients with AIS.

To overcome these challenges, we have developed a functional test that allows us to stratify patients with AIS into three functional subgroups, representing specific endophenotypes. Interestingly, in families with multiple cases of AIS, a specific endophenotype is shared among the affected family members, indicating that such a transmission is inherited. Moreover, increased vulnerability to AIS could be attributable to sustained exposure to osteopontin (OPN), a multifunctional cytokine that appears to be at the origin of the Gi-coupled receptor signalling dysfunction discovered in AIS. We examined the molecular expression profiles of patients with AIS and their response to OPN.

Introduction: Spinal deformities and scoliosis in particular, represent the most prevalent type of orthopaedic deformities in children and adolescents. At present, the most significant problem for clinicians is that there is no proven method or test available to identify children or adolescents at risk of developing AIS or to identify which of the affected individuals are at risk of progression. As a consequence, the application of current treatments, such as bracing or surgical correction, has to be delayed until a significant deformity is detected or until a significant progression is clearly demonstrated, resulting in a delayed and less optimal treatment. Among patients with AIS needing treatment, 80% to 90% will be treated by brace and 10% will need surgery to correct the deformity by spinal instrumentation and fusion of the thoracic and/or lumbar spine. About 15000 such surgeries are done every year in North America, resulting in significant psychological and physical morbidity. Moreover, there is no pharmacotherapy available to either prevent or reduce spinal deformities due mainly to our limited knowledge of AIS aetiopathogenesis. We have recently reconciled the role of melatonin in AIS aetiopathogenesis by demonstrating a melatonin signalling dysfunction occurring in a cell autonomous manner in cells derived from AIS patients exhibiting severe scoliotic deformities. This defect could potentially explain the majority of abnormalities reported in AIS since melatonin receptors and signalling activities are normally found in all tissues and systems affected in AIS, thus offering a very innovative and unifying concept to explain the aetiology of AIS. Moreover, several lines of evidence suggested that inactivation of Gi proteins by an increased phosphorylation of serine residues could be at the source of this signalling defect in AIS. The goals of that study were to assess the possibility to establish a molecular classification of AIS patients and to demonstrate the feasibility to correct this melatonin signalling defect in cells of AIS patients using therapeutic compounds.

Methods: Primary cell cultures were prepared from musculoskeletal tissues of AIS patients (n=150) and age- and gender-matched controls (n=35) obtained intra-operatively. An informed consent was obtained for each subject as approved by our Institutional Ethical Committee. The osteoblasts, the bone-forming cells, were selected to assess whether or not an alteration of melatonin signalling pathway occurs in AIS and accordingly to identify which component of the melatonin transduction machinery could be involved. Co-immunoprecipitation experiments with membrane extracts were performed to identify interacting molecules with key components of melatonin signal transduction machinery. The functionality of melatonin signalling was assessed by investigating the ability of Gi proteins to inhibit stimulated adenyl cyclase activity in osteoblast cultures. Inhibition curves of cAMP production were generated by adding melatonin to the forskolin-containing samples in concentrations ranging from 10-11M to 10-5M in a final volume of 1 ml of _-MEM media containing 0.2% bovine serum albumin (BSA) alone or in presence of 2.5 _M of therapeutic compound A or therapeutic compound B (the nature of both compounds tested cannot be disclosed at this stage). The cAMP content was determined using an enzyme immunoassay kit (Amersham-Pharmacia Biosciences). All assays were performed in duplicate. A non-parametric test, the Wilcoxon matched pairs test was performed to verify the significance between 2 means. Significance was defined as P< 0.05.

Results: Osteoblasts from patients with AIS showed a lack or a markedly reduced inhibition of forskolin-stimulated adenyl cyclase activity by melatonin generating three distinct response-curves corresponding to three functional groups. In order to identify candidate genes involved in AIS aetiopathogenesis, we focused our attention on known kinases and phosphatases modulating Gi protein functions and characterised their interacting partners. Interestingly, PKC_ was initially targeted owing to its property to phosphorylate Gi proteins in vitro. Indeed, in normal osteoblast interactions occurring between MT2 melatonin receptor and RACK1 (a cytosolic protein that bind to and stabilises the actives form of PKC and permits its translocation to different sites within the cells) and PKC_ were detected although those interactions among different AIS patients were altered. Interestingly, treatment with compound A or B rescued melatonin signal defect in cells derived from 36% and 47% of AIS patients respectively. Overall, melatonin signal transduction was restored in cells of 64% of AIS patients (23/36) when treated by one of these therapeutic compounds.

Conclusions: The functional classification of AIS patients is correlated at the molecular level by distinct interactions between key molecules normally involved in melatonin signal transduction in spite that these patients exhibited the same curve type (right thoracic, Lenke type 1). Collectively, these data strongly argue that traditional curve pattern classification is not a relevant stratification of AIS patients to identify its genetic causes. Moreover, using that molecular system we have demonstrated also the possibility to identify therapeutic compounds to rescue the melatonin signalling defect observed in AIS without any prior knowledge of mutations in any defective genes causing AIS because we are measuring a function.

Research project supported by La Fondation Yves Cotrel de l’Institut de France

Medical Genetics is a transversal discipline with the potential to impact on every specialty and subspecialty in medicine and the allied health sciences. The completion of the human genome project resulted in technical advancements in genomics, genomic testing and our understanding of genetic disorders in general. These advancements have greatly enhanced our understanding of the role of genetics in Orthopaedic practice, with respect to both monogenic and complex disorders. Tygerberg Hospital is currently the only state hospital in South Africa to support genetic testing in the form of gene panels as part of routine care. This is complemented by more comprehensive research testing in the form of exome and genome sequencing as part of the Undiagnosed Disease Programme. We audit the genetic and genomic testing done on patients referred from the Orthopaedic clinic over a period of 3 years (2020–2022) and review diagnostic rates and interesting results. The largest group of patients referred (n=50) had a clinical diagnosis of osteogenesis imperfecta (OI). A 100% diagnostic yield was achieved for these patients with the identification of recurring variants (FKBP10, COL1A2). Further families (n=20) with much rarer conditions are presented with important implications on the orthopaedic and medical management, prognosis, and genetic counselling for the families. We highlight the impact of genomic testing in the Orthopaedic clinic. Management changes and precision orthopaedic intervention were only possible due to a genetic diagnosis. We motivate for increased access to testing, especially for younger patients presenting with complex orthopaedic phenotypes

Primary bone tumors are rare, complex and highly heterogeneous. Its diagnostic and treatment are a challenge for the multidisciplinary team. Developments on tumor biomarkers, immunohistochemistry, histology, molecular, bioinformatics, and genetics are fundamental for an early diagnosis and identification of prognostic factors. The personalized medicine allows an effective patient tailored treatment. The bone biopsy is essential for diagnosis. Treatment may include systemic therapy and local therapy. Frequently, a limb salvage surgery includes wide resection and reconstruction with endoprosthesis, biological or composites. The risk for local recurrence and distant metastases depends on the primary tumor and treatment response. Cancer patients are living longer and bone metastases are increasing. Bone is the third most frequently location for distant lesions. Bone metastases are associated to pain, pathological fractures, functional impairment, and neurological deficits. It impacts survival and patient quality of life. The treatment of metastatic disease is a challenge due to its complexity and heterogeneity, vascularization, reduced size and limited access. It requires a multidisciplinary treatment and depending on different factors it is palliative or curative-like treatment. For multiple bone metastases it is important to relief pain and increases function in order to provide the best quality of life and expect to prolong survival. Advances in nanotechnology, bioinformatics, and genomics, will increase biomarkers for early detection, prognosis, and targeted treatment effectiveness. We are taking the leap forward in precision medicine and personalized care

Dupuytren's disease (DD) is a fibroproliferative soft tissue disease affecting the palmar fascia of the hand causing permanent and irreversible flexion contracture. Aberrant fibrosis is likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in soft tissue fibrosis in diseases such as DD is not well established. Therefore, we conducted a comprehensive multi-omic study investigating the epigenetic profiles that influence gene expression in DD pathology. Using control (patients undergoing carpal tunnel release) and diseased fibroblasts (patients undergoing Dupuytren's fasciectomy), we conducted ATAC-seq to assess differential chromatin accessibility between control and diseased fibroblasts. Additionally, ChIP-seq mapped common histone modifications (histone H4; H3K4me3, H3K9me3, H3K27me3, H4K16Ac, H4K20Me3) associated with fibrosis. Furthermore, we extracted RNA from control and DD tissue and performed bulk RNA-seq. ATAC-seq analysis identified 2470 accessible genomic loci significantly more accessible in diseased fibroblasts compared to control. Comparison between diseased and control cells identified numerous significantly different peaks in histone modifications (H4K20me3, H3K27me3, H3K9me3) associated with gene repression in control cells but not in diseased cells. Pathway analysis demonstrated a substantial overlap in genes being de-repressed across these histone modifications (Figure 1). Both, ATAC-seq and ChIP-seq analysis indicated pathways such as cell adhesion, differentiation, and extracellular matrix organisation were dysregulated as a result of epigenetic changes. Moreover, de novo motif enrichment analysis identified transcription factors that possibly contributed to the differential gene expression between control and diseased tissue, including HIC1, NFATC1 and TEAD2. RNA-seq analysis found that these transcription factors were upregulated in DD tissue compared to control tissue. The current epigenetic study provides insights into the aberrant fibrotic processes associated with soft tissue diseases such as DD and indicates that epigenetic-targeted therapies may be an interesting viable treatment option in future. For any figures or tables, please contact the authors directly

Aims. The processes linking long-term bisphosphonate treatment to atypical fracture remain elusive. To establish a means of exploring this link, we have examined how long-term bisphosphonate treatment with prior ovariectomy modifies femur fracture behaviour and tibia mass and shape in murine bones. Methods. Three groups (seven per group) of 12-week-old mice were: 1) ovariectomized and 20 weeks thereafter treated weekly for 24 weeks with 100 μm/kg subcutaneous ibandronate (OVX+IBN); 2) ovariectomized (OVX); or 3) sham-operated (SHAM). Quantitative fracture analysis generated biomechanical properties for the femoral neck. Tibiae were microCT scanned and trabecular (proximal metaphysis) and cortical parameters along almost its whole length measured. Results. Fracture analyses revealed that OVX+IBN significantly reduced yield displacement (vs SHAM/OVX) and resilience, and increased stiffness (vs SHAM). OVX+IBN elevated tibial trabecular parameters and also increased cortical cross-sectional area and second moment of area around minor axis, and diminished ellipticity proximally. Conclusion. These data indicate that combined ovariectomy and bisphosphonate generates cortical changes linked with greater bone brittleness and modified fracture characteristics, which may provide a basis in mice for interrogating the mechanisms and genetics of atypical fracture aetiology. Cite this article: Bone Joint Open 2020;1-9:512–519

Abstract. Objectives. Despite overwhelming need, with about 9 million osteoarthritis (OA) sufferers in UK alone, little progress has been made towards pathogenesis-based categorising of patients and subsequent intervention. Experimental studies relied heavily on animal models, which is inefficient and expensive, and has often produced drugs failing in phase I/II clinical trials due to off-target side effects or failure to predict human disease in animal models. This project aims to address this challenge by developing a scalable in vitro human organotypic tissue model. The model can be used to simulate OA processes and ultimately, exploited to seek biomarkers for early diagnosis or screen potential drugs for efficacy. Methods. We have previously shown that a stratified 3D-tissue akin of articular cartilage can be generated over a 35-day period using a tissue engineering approach with primary human chondrocyte progenitor cells. The engineered tissue mimics native cartilage both in structural organization and biochemical composition. Here, we explore the influence of the nature and homogeneity of initial cell population on cartilage development and maturation. Results. Cell commitment to chondrogenic lineage was found to be a pre-requisite for induction of appropriate appositional growth and stratification of cartilage. Fully differentiated chondrocytes failed to produce a zonated, cartilage-like matrix. Immortalized clonal cell lines were generated, and these were capable of reproducing an appropriate tissue architecture, showing that tissue formation depends on a single progenitor. Conclusion. These findings not only enable generation of human tissue at scale in a highly controlled way, but open up the possibility to consider developmental positional information or genetics within our model

The presentation of musculoskeletal disease differs in men and women, and recognition of the differences between men and women's burden of disease and response to treatment is critical to optimizing care. In this presentation, I will discuss the expanding evidence in the literature that examine the role of sex and gender in musculoskeletal disease, including how its examination increases the innovations and contributions, as well as expands the knowledge about musculoskeletal disease, conditions, and injury in a broad sense. We will discuss the role that structural anatomy differences, hormones, and genetics play in differential disease expression, to the historical biases in the subject populations of clinical and basic research projects. Participants will be provided with examples and opportunities to evaluate orthopaedic science through a sex and gender lens, and what impact this may play in setting the stage for both clinical practice and scientific investigation

Modifiable factors contributing to stiffness include alignment, implant size, implant position and rotation, and soft tissue tightness or laxity. Less modifiable factors include genetics as in predisposition to inflammation and fibrosis, aberrations in perception and experience of emotional pain, and preoperative range of motion. We reviewed 559 knees undergoing revision between 2007 and 2014, selecting out patients with a diagnosis of stiffness and greater than one-year follow-up. Stiffness was defined as greater than 15 degrees of flexion contracture or less than 75 degrees of flexion or less than 90 degrees of active motion and a chief complaint of limited motion and pain. Radiographic analysis used a set of matched controls with greater than 90 degrees and full extension prior to surgery and were further matched by age, gender, BMI. Flexion contracture changed from an average of 9.7 to an average of 2.3 degrees, flexion changed from an average of 81 to an average of 94 degrees, active motion changed from an average of 72 to an average of 92 degrees, pain scores improved from 44 to 72 points, and Knee Society function scores improved from an average of 49 to an average of 70 points. There were four failures for stiffness, two knees underwent additional manipulation, gaining an average of 10 degrees; and two knees were revised. Radiographic analysis demonstrated stiffness to be strongly correlated to anterior condylar offset ratio and to patellar displacement by multivariant regression analysis, suggesting that overstuffing the patellofemoral joint by anteriorization of the femoral component is associated with stiffness. Using modern revision techniques, revision for stiffness creates reliable improvements in pain, Knee Society clinical and functional scores, and motion

Aim. Toxin-antitoxin (TA) systems are small genetics elements found in the majority of bacteria which encode a toxin causing bacterial growth arrest and an antitoxin counteracting the toxic effect. In Salmonella and E. coli, TA systems were shown to be involved in the formation of persisters. Persisters are a bacterial subpopulation with low growth rate and high tolerance to antibiotics. They could be responsible for antibiotic treatment failure in chronic infections and relapses, notably in bone and joint infections (BJI) caused by Staphylococcus aureus. Currently, two type II TA system families were described in S. aureus, mazEF and axe/txe, but their physiological roles are not well described. In this work, we studied the importance of mazEF in the intracellular survival of S. aureus inside osteoblasts, one of the mechanisms considered in the chronicity of S. aureus BJI. Methods. Using an ex vivo model of intracellular infection of human osteoblast-like cells (MG-63), two strains of S. aureus HG003 wild type and its isogenic mutant HG003 ΔmazEF were compared in terms of : i) internalization and intracellular survival by lysostaphin protective assay and ii) cytotoxicity by quantifying LDH in the culture supernatant, 24h and 48h after infection. Results. The comparison of the two strains revealed that HG003 ΔmazEF had a lower capacity to be internalized by osteoblasts compared to the wild type (p=0.02). However, intracellular survival was greater for HG003 ΔmazEF compared to the wild type 24h and 48h post-infection (p=0.02 and 0.001 respectively). Concerning the bacteria-induced cell death, HG003 ΔmazEF appeared to be less cytotoxic than the wild type strain at 24h post infection (p=0.007) whereas no more differences could be observed after 48h. This delayed cytotoxicity with HG003 ΔmazEF was also observed after incubation of culture supernatants with osteoblasts during 8 hours, suggesting that the differences observed could be caused by a secreted molecule. Conclusions. Our results suggest that the mazEF system could be involved in S. aureus BJI physiopathology regulating cytotoxicity and persistence in osteoblasts. Our prospect is to identify the target of the mazF toxin which could be a therapeutic target

Background. The cartilaginous growth plate (GP) is a zonal structure, in which chondrocytes are organized into columns and drive the longitudinal elongation of the endochondral bones. In the proliferative zone (PZ), cells exhibit high mitotic activity, are flattened and oriented along the mediolateral (ML) axis of the GP. Mitotic figures in the elongated chondrocytes lie perpendicular to the proximo-distal (PD) direction of growth, while cell divisions occur parallel to the columns followed by a gliding movement of the daughter cells. The mechanisms responsible for the geometrical anisotropy and columnar arrangement of PZ chondrocytes are poorly understood. Here, we assessed the function of the adhesive receptor β1 integrins on spindle and division geometry in chondrocytes using mouse genetics. Methods. GP slices were prepared from wild type (wt) and β1fl/fl-Col2a1cre mice. Primary rib chondrocytes were cultured on substrate-coated glass slides and fluorescently stained with anti-alpha-tubulin and anti-pericentrin antibodies, with phalloidin and DAPI. Confocal stacks were built from images acquired by confocal microscopy. Cell and spindle orientation relative to the PD axis (in vivo) or to the substrate plane (SP) in vitro were determined by geometric functions. Shape indexes (SI) were calculated as the ratio of the length and height of the cell. Results. During GP morphogenesis, aggregating mesenchymal cells (E11) were polygonal (SI=1.43) and nonoriented. Upon chondrogenic differentiation at E12, wt GP chondrocytes showed moderate flattening (SI=1.93) and tend to align perpendicular to the PD axis. At E13, PZ chondrocytes further flattened (SI=3.41) and largely organized into lines along the ML axis. At E14, the first vertical stacks formed, which were gradually elongated along the PD axis at later stages and composed of extremely flat (SI=4.91), ML-oriented chondrocytes. Early spindles were randomly oriented at all stages, whereas late spindles were aligned along the long axis of the cell. In contrast, β1 integrin null PZ chondrocytes were rounded (SI=1.37), displayed random orientation of both early and late spindles, and failed to organize into columns. On collagen II, both wt and β1-null primary chondrocytes remained rounded and displayed random spindle orientation relative to the SP. On fibronectin (FN), wt chondrocytes were flattened (SI=3.26) and their spindle was aligned parallel to SP. Mutant cells lacking the major FN receptor α5β1 integrin did not spread, were rounded (SI=1.73) and aligned their spindle randomly. On vitronectin, both cell types spread and flattened well (SI=4.11 and SI=4.20) accompanied by parallel spindle orientation to the SP. Conclusion. We propose that β1 integrins provide adhesive cues for chondrocyte geometry and orientation, which in turn orients the mitotic spindle and determines the division axis; and for chondrocyte intercalation to shape the three-dimensional structure of the GP

Systemic concentrations of metal ions (cobalt and chromium) are persistently elevated in patients with metal-on-metal hip resurfacing (MOMHR) compared to conventional total hip arthroplasty (THA). Several studies by us and others have described the detrimental effects of metal exposure on survival and function of various cell types in-vitro, but the mechanisms for these effects remain unclear. Epigenetic modifications following chronic metal exposure is a possible mechanism that could mediate these effects. Here we test the methylation status in genomic DNA from MOMHR (“cases”) and THA (“controls”) patient-groups, and its correlation with circulating metal levels. The cohort consisted of 34 patients with a well-functioning MOMHR at a median follow-up of 9.75 years. These were individually matched for gender, age and time-since-surgery to a non-exposure group consisting of patients with THA. Genomic DNA was isolated from blood samples and cell composition estimated using the ‘estimateCellCounts’ function in ‘minfi R-package’. Methylation was assessed using the Illumina 450k BeadChip array analysing 426,225 probes. Logit model was fitted at each probe with case/control status as independent variable and covariates of gender, age, time-since-surgery, smoking, non-arthroplasty metal exposure, and cell composition. DNA methylation age was assessed using an online calculator (. https://dnamage.genetics.ucla.edu/. ) and comparisons made between cases and controls, and correlated with circulating metal levels. Cell distributions did not differ between the cases and controls (Wilcoxon test p<0.17) with no probe having an association at 5% FDR. Circulating metal levels and LVEDD also had no association with any probe at 5% FDR. There was no preferential age acceleration between cases and controls (Wilcox p<0.7), and it had no correlation with plasma-chromium or blood-cobalt levels (p<0.9). In summary, large methylation changes following MOMHR seem to be absent, compared to THA. Future research with larger samples will be needed to clarify the presence and extent of small methylation changes

Aims

Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease.

Purpose and Background. Low birth weight is related to decreased lumbar spine vertebral canal size and bone mineral content later in life, suggesting that antenatal factors affect spine development. The purpose of this study was to explore associations between antenatal factors and lumbar spine morphology in childhood. Methods. Antenatal data and supine MR images of the lumbar spine were available for 161 children. Shape modelling, using principle components analysis, was performed on mid-sagittal images to quantify different modes of variation in lumbar spine shape. Previously collected measures of spine canal dimensions were analysed. Results. Almost 75 % of all of the variation in lumbar spine shape was explained by just three modes. Modes 1 and 3 described the total amount and the distribution of curvature along the spine, respectively. Mode 2 (M2) captured variation in vertebral shape and size; increasing mode scores represented flatter vertebral bodies with increasing anterior-posterior dimensions. We saw no significant associations between mode scores and birth weight z-scores, placental weight, gestation length and no effect of maternal smoking (P>0.05). Controlling for gestation length revealed a positive correlation between birth weight and M2 (P=0.02). Males, longer babies and those from heavier mothers had higher M2 scores (P<0.05). This sex difference remained even when controlling for the other factors (P<0.001). Modes 1 and 2 correlated with spine canal dimensions (P<0.05). Conclusions. Our results suggest that antenatal factors have some effect on vertebral body morphology but not overall lumbar spinal shape. Perhaps environmental factors during growth and genetics play a larger role in determining the overall spine shape. This abstract has not been previously published in whole or substantial part nor has it been presented previously at a national meeting. Conflicts of interest: No conflicts of interest. Sources of funding: This work was supported by a studentship granted to the University and awarded to AVP

Networks of Excellence (NoE’s) are an instrument to overcome the fragmentation of the European research landscape with the objective to strengthen European excellence in a given area. Their purpose is to reach a durable restructuring/shaping and integration of efforts and institutions or parts of institutions in areas where this is necessary. The success of a NoE is not measured in terms of scientific results but by the extent to which the social fabric for researchers and research institutions in a given field has changed due to the project and the extent to which the existing capacities become more competitive as a result of this change. With that background a “European Network to promote research into uncommon cancers in adults and childrens: Pathology, Biology and Genetics of bone tumours” was initiated and founded by the European Commission in 2005 with the involvement of more than 20 institutions all over Europe. Osteosarcoma research represents an own research line within this network. Up to now a multitude of experience has accumulated over the years which will be presented. The obvious advantages of a close cooperation between the network partners are a major hallmark and success of the network and should further lead to an improved translation of the basic research results towards a clinical application

The purpose of this study was to investigate the role that genetics play in the aetiology and symptomatology of full thickness tears of the rotator cuff. From a retrospective, cohort study of 205 patients diagnosed with full thickness rotator cuff tears, we determined, using ultrasound, the prevalence of full thickness tears in their 129 siblings. Using 150 spouses as controls, the relative risk of full thickness rotator cuff tear in siblings v controls was 2.42 (p< 0.0001, 95 % CI 1.77 to 3.31). The relative risk of symptomatic full thickness rotator cuff tear in siblings v controls was 4.65 (p< 0.0001, 95 % CI 2.42 to 8.63). The significantly increased risk for tears in siblings implies that genetic factors play a major role in the development of full thickness tears of the rotator cuff

While classically bone tumors were classified according to the differentiation and cellular morphology at the light microscopical level, it has become clear that over the past decade the array of knowledge which became available on the cytogenetic and molecular genetic level should influence tumor classification. This lead to an integrated approach in drafting the 2002 WHO nomenclature for bone tumors in which morphology was combined with the evolving genetic information. With regard to bone tumorigenesis distinct patterns can be recognized with regard to underlying genetics:. balanced translocations such as in Ewing sarcoma, or aneurysmal bone cysts. numerical chromosomal abnormalities like in adamantinoma. complex karyotypes with as yet no identified starting point from a genetic point of view such as in osteosarcomas or central chondrosarcomas. single gene events such as in fibrous dysplasia or osteochondroma. These different pathways in oncogenesis open an array of possibilities for studying the drivers in oncogenesis. Especially those pathways essential in keeping the proliferative state as opposed to the ones governing differentiation might proof to be potential targets for tailored drug treatment. Here high throughput screens focusing on kinase activity appear especially of interest. Within the EuroBoNeT consortium (. www.eurobonet.eu. ) several working groups act transnationally together in unraveling these events. Important key elements of study are the molecular-genetic networks involved in skeletogenesis as well, which amongst others are studied within the consortium using in vitro systems as well as in vivo models using xenografted mouse models, mesenchymal stem cell models and models exploring zebrafish development