[Extracorporeal Cardiopulmonary Resuscitation(ECPR) - the Future?] / Extrakorporale kardiopulmonale Reanimation (ECPR) ­ die Zukunft?

In recent years, invasive resuscitation methods utilizing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) have gained significant attention. Despite advances in traditional resuscitation measures, out-of-hospital cardiac arrest (OHCA) mortality remains high. In the context of extracorporeal cardiopulmonary resuscitation (ECPR), VA-ECMO therapy offers a promising approach by providing circulatory support during cardiac arrest, allowing time for diagnostic evaluation and targeted therapy. However, patient selection for ECPR remains a challenge, relying on various factors including initial rhythm, duration of no-flow and low-flow states, as well as presence of reversible causes.Recent studies such as the ARREST, Prague OHCA and INCEPTION trials have investigated the efficacy of ECPR in OHCA patients, yielding mixed results. While the ARREST trial demonstrated a survival benefit with ECPR, the Prague OHCA and INCEPTION trials showed varying outcomes, reflecting the complexity of patient selection and treatment strategies. Despite inherent risks and complications associated with ECPR, it may offer a potential survival advantage under optimal conditions.Future directions in ECPR involve the development of innovative treatment protocols such as the CARL therapy, which incorporates specialized ECMO systems and tailored perfusion solutions. Early studies indicate promising outcomes with CARL therapy, emphasizing the importance of a well-coordinated and structured approach to ECPR implementation.In summary, ECPR shows promise in improving survival rates for OHCA patients within a well-organized healthcare system. However, further research is needed to refine patient selection criteria and optimize treatment protocols, ultimately enhancing patient outcomes in cardiac arrest scenarios.

[Intensive Care in Heart Surgery - is All Now Different?] / Intensivtherapie in der Herzchirurgie ­ alles anders?

With approximately 100000 operations performed in Germany per year, cardiac surgery is among the surgical specialties that require intensive care tratment most frequently. Although all therapeutic aspects of ICU treatment are of high importance among cardiac surgery patients, there is a focus on hemodynamics with the overarching goal of sufficient oxygen delivery. Patients undergoing cardiac surgery are particularily prone to hemodynamic instability and low cardiac output syndrome, potentially culminating into cardiogenic shock. This article presents an overview of essential elements of intensive care medicine in cardiac surgery, paying special attention to hemodynamic monitoring, low cardiac output syndrome, inotropy, cardiac arrhyhmia, perioperative myocardial infarction, and patient blood management.

Measurement of the temporal latency of a respiratory gating system using two distinct approaches.

PURPOSE: To develop a methodology that can be used to measure the temporal latency of a respiratory gating system. METHODS: The gating system was composed of an automatic gating interface (Response) and an in-house respiratory motion monitoring system featuring an optically tracked surface marker. Two approaches were used to measure gating latencies. A modular approach involved measuring separately the latency of the gating system's complementary metal-oxide-semiconductor tracking camera, tracking software, and a gating latency of the LINAC. Additionally, an end-to-end approach was used to measure the total latency of the gating system. End-to-end latencies were measured using the displacement of a radiographic target moving at known velocities during the gating process. RESULTS: Summing together the latencies of each of the modular components investigated yielded a total beam-on latency of 1.55 s and a total beam-off latency of 0.49 s. End-to-end beam-on and beam-off latency was found to be 1.49 and 0.34 s, respectively. In each case, no statistically significant differences were found between the end-to-end latency of the gating system and the summation of the individually measured components. CONCLUSION: Two distinct approaches to quantify gating latencies were presented. Measuring the end-to-end latency of the gating system provided an independent means of validating the modular approach. It is expected that the beam-on latencies reported in this work could be reduced by altering the control system configuration of the LINAC. The modular approach can be used to decouple the individual latencies of the gating system, but future improvements in the temporal resolution of the service graphing feature are needed to reduce the uncertainty of LINAC-related gating latencies measured using this approach. Both approaches are generalizable and can be used together when designing a quality assurance program for a respiratory gating system.

Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior.

We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗20), c.1348C>T (p.Arg450∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.

Vitamin K-Dependent Proteins in Skeletal Development and Disease.

Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology.

Some fluid mechanical constraints on crystallization and recharge within sills.

The injection of hot magma into a sill can lead to heating and melting of the walls and roof of the reservoir while the injected magma cools and crystallizes. If the crystals are relatively dense, they will try to sediment from the injected magma to form a cumulate layer. In this cumulate layer, the crystals form a porous framework which traps the melt as it is built up. As the melt within the sill continually cools and precipitates dense crystals, there will be a gradual reduction in the density of the remaining silicate liquid. As a result, the melt which is progressively trapped in the pore space of the cumulate layer will become stably stratified in density. Using an idealized model of the fluid mechanical and thermodynamical principles, we explore some of the controls on the thickness and density stratification of cumulate layers following replenishment of a sill-like magma chamber. We show the balance between jamming of the crystal laden melt to form a homogeneous layer and the formation of a stratified cumulate zone depends on the cooling time scale compared to the sedimentation time scale. A key finding is that the composition and stratification in a packed crystal-melt suspension and the associated cumulate layer formed by cooling an intrusion of hot melt injected into the crust may have considerable variability, depending on the properties of the overlying roof melt and the size and hence fall speed of crystals which form in the melt. This article is part of the Theo Murphy meeting issue 'Magma reservoir architecture and dynamics'.

Magma chambers versus mush zones: constraining the architecture of sub-volcanic plumbing systems from microstructural analysis of crystalline enclaves.

There are clear microstructural differences between mafic plutonic rocks that formed in a dynamic liquid-rich environment, in which crystals can be moved and re-arranged by magmatic currents, and those in which crystal nucleation and growth are essentially in situ and static. Crystalline enclaves, derived from deep crustal mushy zones and erupted in many volcanic settings, afford a unique opportunity to use the understanding of microstructural development, established from the study of intrusive plutons, to place constraints on the architecture of sub-volcanic systems. Here, we review the relevant microstructural literature, before applying these techniques to interrogate the crystallization environments of enclaves from the Kameni Islands of Santorini and Rábida Volcano in the Galápagos. Crystals in samples of deep-sourced material from both case studies preserve evidence of at least some time spent in a liquid-rich environment. The Kameni enclaves appear to record an early stage of crystallization during which crystals were free to move, with the bulk of crystallization occurring in a static, mushy environment. By contrast, the Rábida enclaves were sourced from an environment in which hydrodynamic sorting and re-arrangement by magmatic currents were common, consistent with a liquid-rich magma chamber. While presently active volcanoes are thought to be underlain by extensive regions rich in crystal mush, these examples preserve robust evidence for the presence of liquid-rich magma chambers in the geological record. This article is part of the Theo Murphy meeting issue 'Magma reservoir architecture and dynamics'.

Absolute Quantification of Noncoding RNA by Microscale Thermophoresis.

Accurate quantification of the copy numbers of noncoding RNA has recently emerged as an urgent problem, with impact on fields such as RNA modification research, tissue differentiation, and others. Herein, we present a hybridization-based approach that uses microscale thermophoresis (MST) as a very fast and highly precise readout to quantify, for example, single tRNA species with a turnaround time of about one hour. We developed MST to quantify the effect of tRNA toxins and of heat stress and RNA modification on single tRNA species. A comparative analysis also revealed significant differences to RNA-Seq-based quantification approaches, strongly suggesting a bias due to tRNA modifications in the latter. Further applications include the quantification of rRNA as well as of polyA levels in cellular RNA.

A new magnet design for future Kibble balances.

We propose a new permanent magnet system for Kibble balance experiments, which combines advantages of the magnet designs invented by the National Physical Laboratory (NPL) and by the Bureau International des Poids et Mesures (BIPM). The goal of the proposed magnet system is to minimize the coil-current effect and to optimize the shielding at the same time. In the proposed design, a permanent magnet system with two gaps, each housing a coil, is employed to minimize the coil current effect, by reducing the linear coil-current dependence reported for the single air gap design by at least one order of magnitude. Both air gaps of the magnet are completely surrounded by high-permeability material, and hence the coils are shielded from outside magnetic fields and no magnetic field leaks outside of the magnet system. An example of the new magnet system is given and the analysis shows that the magnetic field in the air gap can be optimized to meet the requirement to be used in Kibble balances.

Impact of First Eye versus Second Eye Cataract Surgery on Visual Function and Quality of Life.

PURPOSE: To compare the impact of first eye versus second eye cataract surgery on visual function and quality of life. DESIGN: Cohort study. PARTICIPANTS: A total of 328 patients undergoing separate first eye and second eye phacoemulsification cataract surgeries at 5 veterans affairs centers in the United States. Patients with previous ocular surgery, postoperative endophthalmitis, postoperative retinal detachment, reoperation within 30 days, dementia, anxiety disorder, hearing difficulty, or history of drug abuse were excluded. METHODS: Patients received complete preoperative and postoperative ophthalmic examinations for first eye and second eye cataract surgeries. Best-corrected visual acuity (BCVA) was measured 30 to 90 days preoperatively and postoperatively. Patients completed the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ) 30 to 90 days preoperatively and postoperatively. The NEI-VFQ scores were calculated using a traditional subscale scoring algorithm and a Rasch-refined approach producing visual function and socioemotional subscale scores. MAIN OUTCOME MEASURES: Postoperative NEI-VFQ scores and improvement in NEI-VFQ scores comparing first eye versus second eye cataract surgery. RESULTS: Mean age was 70.4 years (±9.6 standard deviation [SD]). Compared with second eyes, first eyes had worse mean preoperative BCVA (0.55 vs. 0.36 logarithm of the minimum angle of resolution (logMAR), P < 0.001), greater mean BCVA improvement after surgery (-0.50 vs. -0.32 logMAR, P < 0.001), and slightly worse postoperative BCVA (0.06 vs. 0.03 logMAR, P = 0.039). Compared with first eye surgery, second eye surgery resulted in higher postoperative NEI-VFQ scores for nearly all traditional subscales (P < 0.001), visual function subscale (-3.85 vs. -2.91 logits, P < 0.001), and socioemotional subscale (-2.63 vs. -2.10 logits, P < 0.001). First eye surgery improved visual function scores more than second eye surgery (-2.99 vs. -2.67 logits, P = 0.021), but both first and second eye surgeries resulted in similar improvements in socioemotional scores (-1.62 vs. -1.51 logits, P = 0.255). CONCLUSIONS: Second eye cataract surgery improves visual function and quality of life well beyond levels achieved after first eye cataract surgery alone. For certain socioemotional aspects of quality of life, second eye cataract surgery results in comparable improvement to first eye cataract surgery.

INS/GNSS Integration for Aerobatic Flight Applications and Aircraft Motion Surveying.

This paper presents field tests of challenging flight applications obtained with a new family of lightweight low-power INS/GNSS (inertial navigation system/global satellite navigation system) solutions based on MEMS (micro-electro-mechanical- sensor) machined sensors, being used for UAV (unmanned aerial vehicle) navigation and control as well as for aircraft motion dynamics analysis and trajectory surveying. One key is a 42+ state extended Kalman-filter-based powerful data fusion, which also allows the estimation and correction of parameters that are typically affected by sensor aging, especially when applying MEMS-based inertial sensors, and which is not yet deeply considered in the literature. The paper presents the general system architecture, which allows iMAR Navigation the integration of all classes of inertial sensors and GNSS (global navigation satellite system) receivers from very-low-cost MEMS and high performance MEMS over FOG (fiber optical gyro) and RLG (ring laser gyro) up to HRG (hemispherical resonator gyro) technology, and presents detailed flight test results obtained under extreme flight conditions. As a real-world example, the aerobatic maneuvers of the World Champion 2016 (Red Bull Air Race) are presented. Short consideration is also given to surveying applications, where the ultimate performance of the same data fusion, but applied on gravimetric surveying, is discussed.

Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis.

OBJECTIVE: Arthritis is a chronic inflammatory disease characterised by immune cell infiltration and mesenchymal cell expansion in the joints. Although the role of immune cells in arthritis is well characterised, the development of mesenchymal cell hyperplasia needs to be better defined. Here, we analysed the role of the ribosomal S6 kinase Rsk2, which we found to be highly activated in joints of patients with arthritis, in the development of mesenchymal cell hyperplasia. METHODS: We genetically inactivated Rsk2 in the tumour necrosis factor (TNF)-α transgenic (TNFtg) mice, an animal model for human inflammatory arthritis. Clinical and histological signs of arthritis as well as molecular markers of inflammation and joint destruction were quantified. Fibroblast-like synoviocytes (FLS) were characterised in vitro and the effect of Rsk2 deletion on the pattern of gene expression was determined. RESULTS: Rsk2 deficiency in TNFtg mice results in earlier and exacerbated inflammation as well as increased bone and cartilage destruction. The production of inflammatory cytokines, matrix metalloproteinases and osteoclastogenic molecules was significantly increased in vivo upon Rsk2 inactivation. Bone marrow deficient in Rsk2 could not transfer this phenotype, indicating that Rsk2 expression in mesenchymal cells controls the course of arthritis. Indeed, Rsk2 deficiency was associated with a more activated phenotype and higher proliferative capacity of FLS, thereby increasing cytokines and production of matrix proteinases. CONCLUSIONS: Rsk2 emerges as a key regulator of mesenchymal cell numbers in the joint and thereby could be targeted to control the inflammatory and tissue-destructive feature of joints in arthritis.

Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis.

OBJECTIVES: Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice. METHODS: Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments. RESULTS: Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1. CONCLUSIONS: Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.

RSK2 protects mice against TNF-induced bone loss.

Tumor necrosis factor (TNF)-α is a key cytokine regulator of bone and mediates inflammatory bone loss. The molecular signaling that regulates bone loss downstream of TNF-α is poorly defined. Here, we demonstrate that inactivating the pro-osteoblastogenic ERK-activated ribosomal S6 kinase RSK2 leads to a drastically accelerated and amplified systemic bone loss in mice ectopically expressing TNF-α [human TNF transgenic (hTNFtg) mice]. The phenotype is associated with a decrease in bone formation because of fewer osteoblasts as well as a drastically increased bone destruction by osteoclasts. The molecular basis of this phenotype is a cell autonomous increased sensitivity of osteoblasts and osteocytes to TNF-induced apoptosis combined with an enhancement of their osteoclast supportive activity. Thus, RSK2 exerts a strong negative regulatory loop on TNF-induced bone loss.

Wnt inhibitory factor 1 deficiency uncouples cartilage and bone destruction in tumor necrosis factor α-mediated experimental arthritis.

OBJECTIVE: Wnt signaling plays a pivotal role in skeletal development and in the control of cartilage and bone turnover. We have recently shown that the secreted Wnt antagonist Wnt inhibitory factor 1 (WIF-1) is mainly expressed in the upper layers of epiphyseal and articular cartilage and, to a lesser extent, in bone. Nevertheless, WIF-1(-/-) mice develop normally. In light of these findings, we undertook this study to analyze the role of WIF-1 in arthritis. METHODS: Expression analyses for WIF-1 were performed by real-time reverse transcription-polymerase chain reaction (RT-PCR). WIF-1(-/-) and tumor necrosis factor (TNF)-transgenic mice were crossbred, and the progression of arthritis in TNF-transgenic WIF-1(-/-) mice and littermate controls was evaluated. Structural joint damage was analyzed by histologic staining, histomorphometry, and micro-computed tomography. Wnt/ß-catenin signaling was investigated by real-time RT-PCR and immunofluorescence on primary chondrocytes. RESULTS: WIF-1 expression was repressed by TNFα in chondrocytes and osteoblasts and down-regulated in experimental arthritis and in articular cartilage from patients with rheumatoid arthritis. WIF-1 deficiency partially protected TNF-transgenic mice against bone erosion and loss of trabecular bone, probably as a result of less osteoclast activity. In contrast, arthritis-related cartilage damage was aggravated by WIF-1 deficiency, while overexpression of WIF-1 attenuated cartilage degradation in TNF-transgenic mice. In chondrocytes, TNFα stimulated canonical Wnt signaling, which could be blocked by WIF-1, indicating a direct effect of TNFα and WIF-1 on Wnt signaling in this system. CONCLUSION: These data suggest that WIF-1 may take part in the fine-tuning of cartilage and bone turnover, promoting the balance of cartilage versus bone anabolism.

Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis.

OBJECTIVE: To test whether inhibition of sclerostin by a targeted monoclonal antibody (Scl-Ab) protects from bone and cartilage damage in inflammatory arthritis. Sclerostin is a potent inhibitor of bone formation and may be responsible for the low level of bone repair in patients with rheumatoid arthritis. METHODS: Human tumour necrosis factor transgenic mice (hTNFtg mice) developing inflammatory arthritis and local and bone loss were administered either vehicle, anti-TNF antibody, Scl-Ab, or a combination of both agents. Inflammation, systemic and periarticular bone loss, bone erosion and cartilage damage were evaluated at baseline (week 8) and after 3 weeks of treatment by clinical assessment, micro-CT and histology. RESULTS: Scl-Ab did not affect joint swelling or synovitis. Systemic bone loss in the spine and periarticular bone loss in the proximal tibia were completely blocked and partially reversed by inhibition of sclerostin but not by inhibition of TNF. Moreover, Scl-Ab completely arrested the progression of bone erosion in hTNFtg mice and in combination with TNF inhibition even led to significant regression of cortical bone erosions. Protective effects of Scl-Ab were also observed for the articular cartilage. CONCLUSIONS: These data suggest that sclerostin inhibition is a powerful tool to enhance bone repair in inflammatory arthritis.

The Wnt antagonist Wif-1 interacts with CTGF and inhibits CTGF activity.

Wnt inhibitory factor 1 (Wif-1) is a secreted antagonist of Wnt signalling. We recently demonstrated that this molecule is expressed predominantly in superficial layers of epiphyseal cartilage but also in bone and tendon. Moreover, we showed that Wif-1 is capable of binding to several cartilage-related Wnt ligands and interferes with Wnt3a-dependent Wnt signalling in chondrogenic cells. Here we provide evidence that the biological function of Wif-1 may not be confined to the modulation of Wnt signalling but appears to include the regulation of other signalling pathways. Thus, we show that Wif-1 physically binds to connective tissue growth factor (CTGF/CCN2) in vitro, predominantly by interaction with the C-terminal cysteine knot domain of CTGF. In vivo such an interaction appears also likely since the expression patterns of these two secreted proteins overlap in peripheral zones of epiphyseal cartilage. In chondrocytes CTGF has been shown to induce the expression of cartilage matrix genes such as aggrecan (Acan) and collagen2a1 (Col2a1). In this study we demonstrate that Wif-1 is capable to interfere with CTGF-dependent induction of Acan and Col2a1 gene expression in primary murine chondrocytes. Conversely, CTGF does not interfere with Wif-1-dependent inhibition of Wnt signalling. These results indicate that Wif-1 may be a multifunctional modulator of signalling pathways in the cartilage compartment.

Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis.

BACKGROUND: Osteophyte formation is a common phenomenon in arthritis. Bone formation by endochondral ossification is considered a key pathophysiological process in the formation of osteophytes. OBJECTIVE: To examine the hypothesis that inhibition of smoothened (Smo), a key component of the hedgehog pathway inhibits osteophyte formation as the hedgehog pathway mediates endochondral ossification. METHODS: Arthritis was induced in 8-week-old C57/BL6 mice by serum transfer (K/BxN model). Mice were then treated by daily administration of either vehicle or LDE223, a specific small molecule inhibitor for Smo, over 2 weeks starting at the onset of disease. Clinical course of arthritis, histological and molecular changes of bone in the affected joints as well as systemic bone changes were assessed. RESULTS: Serum transfer-induced arthritis led to severe osteophyte formation within 2 weeks of onset. Blockade of Smo inhibited hedgehog signalling in vivo and also significantly inhibited osteophyte formation, whereas the clinical and histopathological signs of arthritis were not affected. Also, systemic bone mass did not change. Smo inhibitor particularly blocked the formation of hypertrophic chondrocytes and collagen type X expression. CONCLUSIONS: The data indicate that blockade of hedgehog signalling by targeting Smo specifically inhibits osteophyte formation in arthritis without affecting inflammation and without eliciting bone destruction at the local and systemic level. Blockade of Smo may thus be considered as a strategy to specifically influence the periosteal bone response in arthritis associated with bone apposition.

Wif-1 is expressed at cartilage-mesenchyme interfaces and impedes Wnt3a-mediated inhibition of chondrogenesis.

Wnt factors are involved in the regulation of all steps of cartilage development. The activity of Wnt factors is generally regulated at the extracellular level by factors like the Dkk family, sFRPs, Cerberus and Wnt inhibitory factor 1 (Wif-1). Here we report that Wif-1 is highly expressed at cartilage-mesenchyme interfaces of the early developing skeleton. In fetal and postnatal skeletal development, Wif-1 is expressed in a sharply restricted zone in the upper hyaline layer of epiphyseal and articular cartilage and in trabecular bone. Coimmunoprecipitation and pull-down assays using recombinant Wif-1 and Wnt factors show specific binding of Wif-1 to Wnt3a, Wnt4, Wnt5a, Wnt7a, Wnt9a and Wnt11. Moreover, Wif-1 was able to block Wnt3a-mediated activation of the canonical Wnt signalling pathway. Consequently, Wif-1 impaired growth of mesenchymal precursor cells and neutralised Wnt3a-mediated inhibition of chondrogenesis in micromass cultures of embryonic chick limb-bud cells. These results identify Wif-1 as a novel extracellular Wnt modulator in cartilage biology.

R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway.

OBJECTIVE: During the course of different musculoskeletal diseases, joints are progressively damaged by inflammatory, infectious, or mechanical stressors, leading to joint destruction and disability. While effective strategies to inhibit joint inflammation, such as targeted cytokine-blocking therapy, have been developed during the last decade, the molecular mechanisms of joint damage are still poorly understood. This study was undertaken to investigate the role of the Wnt pathway modulator R-Spondin 1 (RSpo1) in protecting bone and cartilage in a mouse model of arthritis. METHODS: Tumor necrosis factor alpha (TNFalpha)-transgenic mice were treated with vehicle or Rspo1. Mice were evaluated for signs of arthritis, and histologic analysis of the hind paws was performed. Moreover, we determined the effect of Rspo1 on Wnt signaling activity and osteoprotegerin (OPG) expression in murine primary osteoblasts. RESULTS: The secreted Wnt pathway modulator RSpo1 was highly effective in preserving the structural integrity of joints in a TNFalpha-transgenic mouse model of arthritis by protecting bone and cartilage from inflammation-related damage. RSpo1 antagonized the Wnt inhibitor Dkk-1 and modulated Wnt signaling in mouse mesenchymal cells. In osteoblasts, RSpo1 induced differentiation and expression of OPG, thereby inhibiting osteoclastogenesis in vitro. In vivo, RSpo1 promoted osteoblast differentiation and bone formation while blocking osteoclast development, thereby contributing to the integrity of joints during inflammatory arthritis. CONCLUSION: Our results demonstrate the therapeutic potential of RSpo1 as an anabolic agent for the preservation of joint architecture.