Iker Martinez-Zalbidea, Alyssa Rzasa, Varun Puvanesarajah
et al.
Abstract Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promising immunomodulatory properties; however, strategies to enhance their therapeutic potential remain limited. Here, we employed CRISPR activation of the gene TSG-6 in MSCs to evaluate the impact of elevated TSG-6 on EV cargo and immunomodulatory function in an in vitro macrophage model. CRISPR-mediated gene activation was confirmed by RT-qPCR, demonstrating more than an 1800 fold increase in TSG-6 mRNA compared to controls. EVs were isolated from TSG-6 overexpressing MSCs and thoroughly characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blot, confirming their typical size distribution, morphology, and surface markers. Small RNA sequencing of these EVs revealed 15 differentially expressed miRNAs relative to EVs from control MSCs. When THP-1–derived macrophages were stimulated with LPS and treated with TSG-6-overexpressing MSC-EVs (Standard dosage: 1000 particle/cell, n = 11; Alternative dosages: 500, 1000, or 2000 particles/cell, n = 6), a marked reduction in pro-inflammatory cytokine gene expression (IL-1β, CCL2, CXCL10, and TNF-α) and secreted protein levels (CCL2, TNF-α, CXCL1, and MIP-3α) was observed. Taken together, these findings demonstrate that CRISPR-based TSG-6 activation reprograms MSC-EV miRNA cargo (as well as their protein cargo, as previously shown), which can boost their anti-inflammatory effects. These findings underscore the promise of CRISPR-activation as a novel platform for boosting the bioactive properties of MSC-EVs and enhancing immunotherapeutic efficacy.
Michael Silveira Santiago, Fatemeh Akbarpoor, Felipe J. Aidar
et al.
Abstract Background This study compared the long-term efficacy and safety of dual mobility (DM) prostheses versus conventional total hip arthroplasty (c-THA) in femoral neck fracture (FNF) patients. FNFs have a high rate of post-surgical complications, with no consensus on the optimal prosthetic design. This analysis synthesizes the available evidence to address this gap. Methods We systematically searched Cochrane, PubMed, and Embase databases for studies comparing DM and c-THA in FNF patients. Outcomes included dislocation, revision, heterotopic ossification, infection, mortality, peri-prosthetic fracture, quality of life, and functional scores. Relative risk (RR) was used for binary endpoints, while mean differences (MD) or standardized mean differences (SMD) were calculated for continuous endpoints. A random-effects model with a 95% confidence interval (CI) was applied. Statistical analyses were conducted using R version 4.4.0. Results We included three randomized controlled trials and ten cohort studies, amounting to 21,585 patients, of which 4887 received and 16,698 received c-THA. Compared to c-THA, DM showed lower dislocation (RR 0.47; 95% CI: 0.34–0.65; p < 0.001) and revision rates (RR 0.77; 95% CI: 0.67–0.89; p < 0.001) but higher heterotopic ossification (RR 1.98; 95% CI: 1.22–3.20; p < 0.05) and worse functional scores at six to nine months (SMD 1.65; 95% CI: 0.75–2.55; p < 0.001). Meta-regression analysis showed no impact of the posterior approach on dislocation outcomes (p = 0.76). Conclusion DM reduces dislocation and revision risks but increases heterotopic ossification and shows worse short-term functional outcomes. Larger randomized trials are needed to validate long-term efficacy and safety.
Orthopedic surgery, Diseases of the musculoskeletal system
Introduction:
Cleft hands and feet constitute a rare, congenital abnormality of limb bud development, manifesting as a cosmetically and, occasionally, a functional debility of the hands or feet. Patients often pursue expert advice regarding the surgical reconstruction of their deformities, which may pose an ethical dilemma to the treating practitioner.
Case Report:
We present a case series of a family of three with bilateral cleft hands and feet, highlighting the dissimilarities in their phenotypic presentation. The clinical pointers indicate a possible syndromic association of ectrodactyly, ectodermal dysplasia, and clefting syndrome.
Management:
All patients were evaluated for the possibility of surgical reconstruction of their deformities, and were managed non-operatively in view of their satisfactory functional adaptation.
Conclusion:
The present report highlights the clinical features, diagnosis, and role of a multidisciplinary approach in the evaluation of this culturally disconcerting disorder. Surgery should be reserved for severe functional limitation in case of cleft hands and unadaptable cleft feet.
Orthopedic surgery, Diseases of the musculoskeletal system
Abstract Background Gout is a prevalent manifestation of metabolic osteoarthritis induced by elevated blood uric acid levels. The purpose of this study was to investigate the mechanisms of gene expression regulation in gout disease and elucidate its pathogenesis. Methods The study integrated gout genome-wide association study (GWAS) data, single-cell transcriptomics (scRNA-seq), expression quantitative trait loci (eQTL), and methylation quantitative trait loci (mQTL) data for analysis, and utilized two-sample Mendelian randomization study to comprehend the causal relationship between proteins and gout. Results We identified 17 association signals for gout at unique genetic loci, including four genes related by protein-protein interaction network (PPI) analysis: TRIM46, THBS3, MTX1, and KRTCAP2. Additionally, we discerned 22 methylation sites in relation to gout. The study also found that genes such as TRIM46, MAP3K11, KRTCAP2, and TM7SF2 could potentially elevate the risk of gout. Through a Mendelian randomization (MR) analysis, we identified three proteins causally associated with gout: ADH1B, BMP1, and HIST1H3A. Conclusion According to our findings, gout is linked with the expression and function of particular genes and proteins. These genes and proteins have the potential to function as novel diagnostic and therapeutic targets for gout. These discoveries shed new light on the pathological mechanisms of gout and clear the way for future research on this condition.
Abstract Background Osteoporotic fractures (OPF) are fractures that occur with low-energy injuries or during daily activities, representing a serious consequence of osteoporosis (OP). With the worsening of population aging, the number of OPF patients continues to expand, causing a significant burden on families and society. Consequently, it is significant to diagnose and analyze OPF at the molecular level. Objective The aim of this research was to explore the diagnostic value of miR-32-3p in OPF patients and to exploit new biomarkers for clinical applications. Methods The miR-32-3p expression level of patients was detected by RT-qPCR. Diagnostic accuracy of miR-32-3p analyzed adopting ROC curve. Additionally, the risk factors correlation with the occurrence of OPF were assessed by logistic analysis. The effect of miR-32-3p on BMSCs was verified by in vitro transfection experiments. Results miR-32-3p expression was lower in OPF patients than in OP patients. ROC curve implied that miR-32-3p exhibits commendable sensitivity (88.9%) and specificity (75.6%) to differentiate between OP and OPF patients (AUC = 0.905, P < 0.001). Furthermore, miR-32-3p was correlated with the development of OPF and was a risk factor for OPF (P < 0.001). Functional assays revealed that transfection with miR-32-3p mimic could promote proliferation and inhibit apoptosis, whereas transfection with miR-32-3p inhibitor had the opposite effect. Conclusion miR-32-3p demonstrates significant diagnostic potential for OPF patients. It is likely that miR-32-3p probably is a new diagnosis biomarker for OPF, offering promising therapeutic avenues through targeted interventions.
Orthopedic surgery, Diseases of the musculoskeletal system
Richard D. M. Stevenson, Enhad A. Chowdhury, Victor B. Inza
et al.
Abstract Background Knee osteoarthritis is one of the most prevalent long term health conditions globally. Exercise and physical activity are now widely recognised to significantly reduce joint pain, improve physical function and quality of life in patients with knee osteoarthritis. However, prescribed exercise without regular contact with a healthcare professional often results in lower adherence and poorer health outcomes. Digital mobile health (mHealth) technologies offer great potential to support people with long-term conditions such as knee osteoarthritis more efficiently and effectively and with relatively lower cost than existing interventions. However, there are currently very few mHealth interventions for the self-management of knee osteoarthritis. The aim of the present study was to describe the development process of a mHealth app to extend the support for physical activity and musculoskeletal health beyond short-term, structured rehabilitation through self-management, personalised physical activity, education, and social support. Methods The development of the intelligent knee osteoarthritis lifestyle application intervention involved an iterative and interconnected process comprising intervention ‘planning’ and ‘optimisation’ informed by the person-based approach framework for the development of digital health interventions. The planning phase involved a literature review and collection of qualitative data obtained from focus groups with individuals with knee osteoarthritis (n = 26) and interviews with relevant physiotherapists (n = 5) to generate ‘guiding principles’ for the intervention. The optimisation phase involved usability testing (n = 7) and qualitative ‘think aloud’ sessions (n = 6) with potential beneficiaries to refine the development of the intervention. Results Key themes that emerged from the qualitative data included the need for educational material, modifying activities to suit individual abilities and preferences as well as the inclusion of key features such as rehabilitation exercises. Following a user-trial further changes were made to improve the usability of the application. Conclusions Using a systematic person-based, development approach, we have developed the intelligent knee osteoarthritis lifestyle application to help people maintain physical activity behaviour. The app extends the support for physical activity and musculoskeletal health beyond short-term, structured rehabilitation through personalised physical activity guidance, education, and social support.
Faeze Dehghan Banadaki, Benyamin Rahimian, Fatemeh Moraveji
et al.
Abstract Background Excessive smartphone usage among students can lead to discomfort in their hands and fingers. This study investigates the impact of smartphone holding posture, duration of usage, and the prevalence of wrist and finger pain among university students. Methods This cross-sectional study involved 213 university students who were selected based on inclusion criteria. Data was collected through a demographic information questionnaire. Participants self-reported five different postures for holding and interacting with a smartphone. The prevalence, frequency, severity, and interference of wrist and finger discomfort were assessed using the Cornell Hand Discomfort Questionnaires (CHDQ). Results The study revealed that the average age of participants was 21.3 ± 2.2 years. On average, they had been using smartphones for 7.9 ± 3.1 years and spent an average of 4.9 ± 2.5 h daily holding them in their hands. In terms of discomfort, more than 25% of students reported pain in areas C (thumb finger), E (Palm Pollicis), and F (wrist) of the right hand, which was significantly related to the duration of holding the smartphone in that hand. Additionally, smartphone holding duration significantly affected areas D (palm) and F of the left hand, with over 11% of students experiencing discomfort. The most prevalent posture among students (41% of participants) involved holding the smartphone with the right hand only, with the thumb touching the screen. Notably, areas B (χ2 = 21.7), C (χ2 = 10.27), D (χ2 = 65.54), and E (χ2 = 59.49) of the right hand, as well as areas C (χ2 = 6.58) and E (χ2 = 44.28) of the left hand, exhibited significant associations with the postures of holding the smartphone. Conclusions The duration of smartphone use and the postures in which it is held contribute to the prevalence of discomfort in the thumb area and related muscles among right-handed students.
<b>Background/Objectives</b>: Resistance training (RT) can improve the functional performance of older adults, maintaining independence and quality of life. It has been proposed that training interventions should implement exercises associated with the movements needed in everyday life. However, this strength training philosophy presents challenges, specifically to older adults, and the use of resistance machines might present an efficacious alternative. The aim of this systematic review and meta-analysis was to explore the impact of machine-based RT on strength and functional capacity in older adults. <b>Methods</b>: The inclusion criteria were for strength training interventions to be a minimum of 6 weeks, using only resistance machines, with pre- and post-intervention measurements of functional capacity of either a timed up-and-go and/or a sit-to-stand test, and including healthy older adults (>60 years). <b>Results</b>: Following the screening, 17 articles met the inclusion criteria for the systematic review, 15 of which were included in the meta-analysis for functional outcomes (n = 614 participants), and 11 of which were included in the meta-analysis for strength outcomes (n = 511 participants). Analyses revealed significant standardized mean change in favor of machine-based RT for functional outcomes (0.72, 95% CIs 0.39 to 1.07) and strength outcomes (0.71, 95% CIs 0.34 to 1.08) compared to control conditions (functional = 0.09, 95% CIs − 0.1 to 0.28, strength = 0.1, 95% CIs − 0.05 to 0.24). Substantial heterogeneity was noted in the manipulation of RT variables and the magnitude of effects between studies. <b>Conclusions</b>: The data presented support the idea that significant strength and functional performance outcomes are attainable using uncomplicated, machine-based RT.
Masakazu Toya, Junichi Kushioka, Huaishuang Shen
et al.
Aims: Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice. Methods: We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR). Results: Local delivery of NF-κB decoy ODN in vivo increased osteogenesis in males, but not females, in the presence of chronic inflammation induced by cPE. Bone resorption activity was decreased in both sexes. In vitro osteogenic and osteoclastic differentiation assays during inflammatory conditions did not reveal differences among the groups. Receptor activator of nuclear factor kappa Β ligand (Rankl) gene expression by osteoblasts was significantly decreased only in males when treated with ODN. Conclusion: We demonstrated that NF-κB decoy ODN increased osteogenesis in male mice and decreased bone resorption activity in both sexes in preclinical models of chronic inflammation. NF-κB signalling could be a therapeutic target for chronic inflammatory diseases involving bone, especially in males. Cite this article: Bone Joint Res 2024;13(1):28–39.
Grace H. Lo, Surabhi Vinod, Michael J. Richard
et al.
ObjectiveTo assess the relationship between walking for exercise and symptomatic and structural disease progression in individuals with knee osteoarthritis (OA).MethodsWe assessed a nested cohort of participants age 50 years or older within the Osteoarthritis Initiative, a community‐based observational study in which subjects were enrolled between 2004 and 2006. We focused on 4 dichotomous outcomes from baseline to the 48‐month visit, involving determination of the frequency of knee pain and radiographic severity of knee OA on posteroanterior semiflexed knee radiographs. The outcomes assessed included 1) new frequent knee pain, 2) worsening of radiographic severity of knee OA based on the Kellgren/Lawrence grade, 3) progression of medial joint space narrowing, and 4) improved frequent knee pain. We used a modified version of the Historical Physical Activity Survey Instrument to ascertain those subjects who reported walking for exercise after age 50 years. The survey was administered at the 96‐month visit (2012–2014).ResultsOf 1,212 participants with knee OA, 45% were male and 73% reported walking for exercise. The mean ± SD age was 63.2 ± 7.9 years, and the mean ± SD body mass index was 29.4 ± 4.6 kg/m2. The likelihood of new frequent knee pain was reduced in participants with knee OA who walked for exercise as compared to those who were non‐walkers (odds ratio [OR] 0.6, 95% confidence interval [95% CI] 0.4–0.8), and progression of medial joint space narrowing was less common in walkers compared to non‐walkers (OR 0.8, 95% CI 0.6–1.0).ConclusionIn individuals with knee OA who were age 50 years or older, walking for exercise was associated with less frequent development of knee pain. These findings support the notion that walking for exercise should be encouraged for people with knee OA. Furthermore, we offer a proof of concept that walking for exercise could be disease modifying, which warrants further study.
Medical science does not treat death as an independent physiological phenomenon. It believes that disease is the cause of death and treats both as preventable phenomena. Doctors and relatives nurture a guilt complex when death occurs. The moment of natural death is robbed of its poignancy. There is no cause of death. Death of the physical body is an intrinsic, time governed, built-in ontolytic program. It completes the biologic trajectory of the individual organism which begins at conception and ends with death. In this article, the actual built-in mechanism and operation of the physiological process of death is suggested vis-a-vis biology and medicine. The physical body of an individual is like a biological gadget which is constantly charged with life force received from cosmic energy through the subtle body which is an implement that cannot be objectified in the same way as the gross physical body but is experienced only subjectively by one and all, as mind (antahkaran in Sanskrit and Indian languages, meaning inner instrument, a subtler instrument in contrast to external organs of actions like limbs, tongue, etc. of the physical body). This life force keeps the subtle body and the entire physical body live and functioning. It maintains the body's integrity and internal homeostasis throughout life. The physical body like a gadget has a built-in program which decides how much total capacity, pace and quantum of life force it can use. It is often referred to as breath quota and heartbeat quota, however, they are manifestations and not the mechanism and operation of life and death in the physical body. When the quantum of life force of the physical body is exhausted, the subtle body, a connector for life forces departs, leaving behind the physical body. The vital functions stop and the person is declared dead. It is usually referred to as departure of soul (Pran or Jiva in India) from the physical body in common parlance. This phenomenon of predetermined capacity, pace and fixed quota of life force is operational in all the components of the body. Each cell, each organ, each system and the whole body is a packed unit of bioenergy. They are in structural and functional dynamic homeostasis under constant flux resulting in constant change in the body. The rate of expenditure contributes towards deciding the total life span of the cell, organ, systems and individual. It accounts for the phenomena of cell death, progressive diminution in vitality, change in organ and system functions during life and physical death of an individual at the end. Death is a bio-cosmic phenomenon governed by biological laws. There is variation in life span at the interspecies and intraspecies levels because we measure lifespan of an individual in terms of physical time and not in terms of biological time which is an independent entity, not measurable and predictable as physical time. Everyone lives one full unit of life in terms of biological time which begins at conception and ends with death. The normal distribution of each biological feature, including the biological unit of life, is independent of one another making each individual unique. The biological clock runs at its own dynamic unique pace in every individual. The biological timer starts ticking at conception and stops when the life force quantum is over. When the person dies, the physical body stops functioning and is left behind for others to dispose of. The timing of death is beyond the realm of objective perception and cannot be equated with chronological or physical time. It is a trans-science and trans-technique phenomenon beyond the ken of humankind to alter its mechanism and operation. The article explains the impact of extrinsic and intrinsic diseases, various treatments such as organ transplant, as well as the impact of lifestyle on the biological time scale of an individual. It spells out the difference between natural and unnatural death. With this understanding, death can be appreciated, accepted and respected as a built-in operational intrinsic physiological phenomenon for the end of one's life. It is a must for the survival and healthy continuity of all the species in the biological world including mankind.
Moustafa Ali Saad, Hamdy Ahmed, Rasmia Elgohary
et al.
Abstract Background IgG4-related disease (IgG4-RD) is a progressive and sometimes fatal disease that rarely affects pediatric age group. It may affect the orbits, lacrimal and salivary glands, pancreas, kidneys, peritoneum and other organs. Lung and pleura are not commonly reported in IgG4-RD. We here present a rare case of pediatric IgG4-RD with rare involvement of pericardium, pleura and lungs. Case presentation A 13-year-old girl presented with intrathoracic IgG4-RD with pleuropericardial involvement. She showed initial improvement on prednisolone. Azathioprine and then mycophenolate failed to control relapses during steroid tapering. Her last relapse was treated by rituximab however, the patient developed acute fatal massive hemoptysis. Conclusions Pediatric IgG4-RD is a rare entity with pericardio-pulmonary affection as the rare of the rare. Usual treatment of prednisolone and steroid sparing agents should be used, with rituximab used as a rescue therapy, but fatal complications may occur.
Pediatrics, Diseases of the musculoskeletal system
Daniel Dornacher, Maximilian Kelsch, Mirco Sgroi
et al.
Abstract Purpose The aim of this examination was to assess whether there is a change of acetabular correction after triple pelvic osteotomy (TPO) and if so, whether there is a correlation with patient-specific risk factors or with certain periods in the postoperative course. Methods A consecutive series of 241 TPO was reviewed retrospectively. The close-meshed radiographic follow-up of the first 12 weeks comprised pelvic radiographs performed immediately after the procedure, 5 days, 6 and 12 weeks after TPO. Three observers measured the lateral center edge angle, acetabular index and the craniocaudal offset of the pubic osteotomy. Patient-specific risk factors (e. g. age, gender, body mass index, nicotine abuse) and certain periods in the postoperative course were correlated with a change of acetabular correction. Results After application of the exclusion criteria, 225 hips were available for further examination. Intraclass correlation coefficient resulted in predominantly excellent agreement between the measurements of the three observers (0.74–0.91). In 27 cases (12%), the three observers agreed on a change of acetabular correction. In 18 cases (8%), there was a slight change, in 9 cases (4%), a relevant change. The latter entailed consequences in the postoperative aftercare. General equation estimation did not show any correlation between a change of acetabular correction and patient-specific risk factors or certain periods in the postoperative course (p = 0.79–0.99). Conclusion Every once treated hip should be followed-up with the same attention, irrespective of the apparent risk profile. There is no rationale to skip a radiographic follow-up in the first 12 weeks after TPO.
Orthopedic surgery, Diseases of the musculoskeletal system
Rubens Sautchuk, Brianna H Kalicharan, Katherine Escalera-Rivera
et al.
Cyclophilin D (CypD) promotes opening of the mitochondrial permeability transition pore (MPTP) which plays a key role in both cell physiology and pathology. It is, therefore, beneficial for cells to tightly regulate CypD and MPTP but little is known about such regulation. We have reported before that CypD is downregulated and MPTP deactivated during differentiation in various tissues. Herein, we identify BMP/Smad signaling, a major driver of differentiation, as a transcriptional regulator of the CypD gene, Ppif . Using osteogenic induction of mesenchymal lineage cells as a BMP/Smad activation-dependent differentiation model, we show that CypD is in fact transcriptionally repressed during this process. The importance of such CypD downregulation is evidenced by the negative effect of CypD ‘rescue’ via gain-of-function on osteogenesis both in vitro and in a mouse model. In sum, we characterized BMP/Smad signaling as a regulator of CypD expression and elucidated the role of CypD downregulation during cell differentiation.
Despite major progress in the understanding of the pathophysiology and therapeutic options for common ageing-related musculoskeletal conditions (i.e. osteoporosis and associated fractures, sarcopenia and osteoarthritis), there is still a considerable proportion of patients who respond sub optimally to available treatments or experience adverse effects. Emerging microbiome research suggests that perturbations in microbial composition, functional and metabolic capacity (i.e. dysbiosis) are associated with intestinal and extra-intestinal disorders including musculoskeletal diseases. Besides its contributions to disease pathogenesis, the role of the microbiome is further extended to shaping individuals’ responses to disease therapeutics (i.e. pharmacomicrobiomics). In this review, we focus on the reciprocal interactions between the microbiome and therapeutics for osteoporosis, sarcopenia and osteoarthritis. Specifically, we identify the effects of therapeutics on microbiome’s configurations, functions and metabolic output, intestinal integrity and immune function, but also the effects of the microbiome on the metabolism of these therapeutics, which in turn, may influence their bioavailability, efficacy and side-effect profile contributing to variable treatment responses in clinical practice. We further discuss emerging strategies for microbiota manipulation as preventive or therapeutic (alone or complementary to available treatments) approaches for improving outcomes of musculoskeletal health and disease.
Aberrant NF-κB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-κB signaling can be modeled in transgenic mice upon activation of a conditional NF-κB-inducing kinase (NIK) allele lacking the regulatoryTRAF3binding domain (NT3). Here, we report that expression ofNT3in the mesenchymal lineage withOsterix (Osx/Sp7)-CreorFibroblast-Specific Protein 1 (FSP1)-Crecaused subcutaneous, soft tissue tumors. These tumors displayed significantly shorter latency and a greater multiple incidence rate inFsp1-Cre;NT3compared toOsx-Cre;NT3mice, regardless of sex. Histological assessment revealed poorly differentiated solid tumors with some spindled patterns, as well as robust RelB immunostaining, confirming activation of alternative NF-κB. Even thoughNT3expression also occurs in the osteolineage inOsx-Cre;NT3mice, we observed no bony lesions. The staining profiles and pattern ofCreexpression in the two lines pointed to a mesenchymal tumor origin. Immunohistochemistry revealed that these tumors stain strongly for alpha-smooth muscle actin (αSMA), although vimentin staining was uniform only inOsx-Cre;NT3tumors. Negative CD45 and S100 immunostains precluded hematopoietic and melanocytic origins, respectively, while positive staining for cytokeratin 19 (CK19), typically associated with epithelia, was found in subpopulations of both tumors. Principal component, differential expression, and gene ontology analyses revealed thatNT3tumors are distinct from normal mesenchymal tissues and are enriched for NF-κB related biological processes. We conclude that constitutive activation of the alternative NF-κB pathway in the mesenchymal lineage drives spontaneous sarcoma and provides a novel mouse model for NF-κB related sarcomas.