The role of YAP/TAZ on joint and arthritis.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common forms of arthritis with undefined etiology and pathogenesis. Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ), which act as sensors for cellular mechanical and inflammatory cues, have been identified as crucial players in the regulation of joint homeostasis. Current studies also reveal a significant association between YAP/TAZ and the pathogenesis of OA and RA. The objective of this review is to elucidate the impact of YAP/TAZ on different joint tissues and to provide inspiration for further studying the potential therapeutic implications of YAP/TAZ on arthritis. Databases, such as PubMed, Cochran Library, and Embase, were searched for all available studies during the past two decades, with keywords "YAP," "TAZ," "OA," and "RA."

Increased interleukin-26 in the peripheral joints of patients with axial spondyloarthritis and psoriatic arthritis, co-localizing with CD68-positive synoviocytes.

Objectives: IL26 levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. IL26 can be produced by Th17 cells and locally within joints by tissue-resident cells. IL26 induces osteoblast mineralization in vitro. As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of IL26 in spondyloarthritis. Methods: Serum, peripheral blood mononuclear cells (n = 15-35) and synovial tissue (n = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, n = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR. Results: Synovial tissue of axSpA patients shows significantly more IL26-positive cells than that of HCs (p < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of IL26 with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. IL26 is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs (p < 0.001 and p < 0.01). However, peripheral blood CD4+ T cells from axSpA and PsA patients show higher positivity for IL26 in the PrimeFlow assay compared with HCs. CD4+ memory T cells from axSpA patients produce more IL26 under Th17-favoring conditions (IL-1ß and IL-23) than cells from PsA and RA patients or HCs. Conclusion: IL26 production is increased in the synovial tissue of SpA and can be localized to CD68+ macrophage-like synoviocytes, whereas circulating IL26+ Th17 cells are only modestly enriched. Considering the osteoproliferative properties of IL26, this offers new therapeutic options independent of Th17 pathways.

Joint-specific memory, resident memory T cells and the rolling window of opportunity in arthritis.

In rheumatoid arthritis, juvenile idiopathic arthritis and other forms of inflammatory arthritis, the immune system targets certain joints but not others. The pattern of joints affected varies by disease and by individual, with flares most commonly involving joints that were previously inflamed. This phenomenon, termed joint-specific memory, is difficult to explain by systemic immunity alone. Mechanisms of joint-specific memory include the involvement of synovial resident memory T cells that remain in the joint during remission and initiate localized disease recurrence. In addition, arthritis-induced durable changes in synovial fibroblasts and macrophages can amplify inflammation in a site-specific manner. Together with ongoing systemic processes that promote extension of arthritis to new joints, these local factors set the stage for a stepwise progression in disease severity, a paradigm for arthritis chronicity that we term the joint accumulation model. Although durable drug-free remission through early treatment remains elusive for most forms of arthritis, the joint accumulation paradigm defines new therapeutic targets, emphasizes the importance of sustained treatment to prevent disease extension to new joints, and identifies a rolling window of opportunity for altering the natural history of arthritis that extends well beyond the initiation phase of disease.

[Design and support performance evaluation of medical multi-position auxiliary support exoskeleton mechanism].

Aiming at the status of muscle and joint damage caused on surgeons keeping surgical posture for a long time, this paper designs a medical multi-position auxiliary support exoskeleton with multi-joint mechanism by analyzing the surgical postures and conducting conformational studies on different joints respectively. Then by establishing a human-machine static model, this study obtains the joint torque and joint force before and after the human body wears the exoskeleton, and calibrates the strength of the exoskeleton with finite element analysis software. The results show that the maximum stress of the exoskeleton is less than the material strength requirements, the overall deformation is small, and the structural strength of the exoskeleton meets the use requirements. Finally, in this study, subjects were selected to participate in the plantar pressure test and biomechanical simulation with the man-machine static model, and the results were analyzed in terms of plantar pressure, joint torque and joint force, muscle force and overall muscle metabolism to assess the exoskeleton support performance. The results show that the exoskeleton has better support for the whole body and can reduce the musculoskeletal burden. The exoskeleton mechanism in this study better matches the actual working needs of surgeons and provides a new paradigm for the design of medical support exoskeleton mechanism.

Determining a musculoskeletal system's pre-stretched state using continuum-mechanical forward modelling and joint range optimization.

The subject-specific range of motion (RoM) of a musculoskeletal joint system is balanced by pre-tension levels of individual muscles, which affects their contraction capability. Such an inherent pre-tension or pre-stretch of muscles is not measureable with in vivo experiments. Using a 3D continuum mechanical forward simulation approach for motion analysis of the musculoskeletal system of the forearm with 3 flexor and 2 extensor muscles, we developed an optimization process to determine the muscle fibre pre-stretches for an initial arm position, which is given human dataset. We used RoM values of a healthy person to balance the motion in extension and flexion. The performed sensitivity study shows that the fibre pre-stretches of the m. brachialis, m. biceps brachii and m. triceps brachii with 91 % dominate the objective flexion ratio, while m. brachiradialis and m. anconeus amount 7.8 % and 1.2 % . Within the multi-dimensional space of the surrogate model, 3D sub-spaces of primary variables, namely the dominant muscles and the global objective, flexion ratio, exhibit a path of optimal solutions. Within this optimal path, the muscle fibre pre-stretch of two flexors demonstrate a negative correlation, while, in contrast, the primary extensor, m. triceps brachii correlates positively to each of the flexors. Comparing the global optimum with four other designs along the optimal path, we saw large deviations, e.g., up to 15 ∘ in motion and up to 40% in muscle force. This underlines the importance of accurate determination of fibre pre-stretch in muscles, especially, their role in pathological muscular disorders and surgical applications such as free muscle or tendon transfer.

Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints.

Osteoarthritis (OA) is a painful, incurable disease affecting over 500 million people. Recent clinical trials of the nerve growth factor (NGF) inhibitors in OA patients have suggested adverse effects of NGF inhibition on joint structure. Here we report that nerve growth factor receptor (NGFR) is upregulated in skeletal cells during OA and plays an essential role in the remodeling and repair of osteoarthritic joints. Specifically, NGFR is expressed in osteochondral cells but not in skeletal progenitor cells and induced by TNFα to attenuate NF-κB activation, maintaining proper BMP-SMAD1 signaling and suppressing RANKL expression in mice. NGFR deficiency hyper-activates NF-κB in murine osteoarthritic joints, which impairs bone formation and enhances bone resorption as exemplified by a reduction in subchondral bone and osteophytes. In human OA cartilage, NGFR is also negatively associated with NF-κB activation. Together, this study suggests a role of NGFR in limiting inflammation for repair of diseased skeletal tissues.

Reliability assessment of the OMERACT whole-body magnetic resonance imaging scoring system for juvenile idiopathic arthritis.

Inter-reader reliability of a new scoring system for evaluating joint inflammation and enthesitis in whole body MRI (WBMRI) in juvenile idiopathic arthritis was tested. The scoring system grades 732 item-region combinations of bone marrow and soft tissue changes for commonly involved joints and entheseal sites. Five radiologists rated 17 WBMRI scans through an online rating platform. Item-wise reliability was calculated for 117 items with non-zero scores in >10 % of readings. Interquartile ranges of the five-reader Kappa reliability coefficients were 0.58-0.73 (range: 0.36-0.88) for the joints, 0.65-0.81 (range: 0.39-0.95) for the entheses, and 0.62-0.75 (range: 0.60-0.76) for chronic nonbacterial osteomyelitis-like lesions.

Shape variation and sex differences of the adult human mandible evaluated by geometric morphometrics.

In cases of osseous defects, knowledge of the anatomy, and its age and sex-related variations, is essential for reconstruction of normal morphology. Here, we aimed at creating a 3D atlas of the human mandible in an adult sample using dense landmarking and geometric morphometrics. We segmented 50 male and 50 female mandibular surfaces from CBCT images (age range: 18.9-73.7 years). Nine fixed landmarks and 510 sliding semilandmarks were digitized on the mandibular surface, and then slid by minimizing bending energy against the average shape. Principal component analysis extracted the main patterns of shape variation. Sexes were compared with permutation tests and allometry was assessed by regressing on the log of the centroid size. Almost 49 percent of shape variation was described by the first three principal components. Shape variation was related to width, height and length proportions, variation of the angle between ramus and corpus, height of the coronoid process and inclination of the symphysis. Significant sex differences were detected, both in size and shape. Males were larger than females, had a higher ramus, more pronounced gonial angle, larger inter-gonial width, and more distinct antegonial notch. Accuracy of sexing based on the first two principal components in form space was 91 percent. The degree of edentulism was weakly related to mandibular shape. Age effects were not significant. The resulting atlas provides a dense description of mandibular form that can be used clinically as a guide for planning surgical reconstruction.

Computational modelling of articular joints with biphasic cartilage: recent advances, challenges and opportunities.

Biphasic models have been widely used to simulate the time-dependent biomechanical response of soft tissues. Modelling techniques of joints with biphasic weight-bearing soft tissues have been markedly improved over the last decade, enhancing our understanding of the function, degenerative mechanism and outcomes of interventions of joints. This paper reviews the recent advances, challenges and opportunities in computational models of joints with biphasic weight-bearing soft tissues. The review begins with an introduction of the function and degeneration of joints from a biomechanical aspect. Different constitutive models of articular cartilage, in particular biphasic materials, are illustrated in the context of the study of contact mechanics in joints. Approaches, advances and major findings of biphasic models of the hip and knee are presented, followed by a discussion of the challenges awaiting to be addressed, including the convergence issue, high computational cost and inadequate validation. Finally, opportunities and clinical insights in the areas of subject-specific modeling and tissue engineering are provided and discussed.

Functions and Metabolism of Amino Acids in Bones and Joints of Cats and Dogs.

The bone is a large and complex organ (12-15% of body weight) consisting of specialized connective tissues (bone matrix and bone marrow), whereas joints are composed of cartilage, tendons, ligaments, synovial joint capsules and membranes, and a synovial joint cavity filled with synovial fluid. Maintaining healthy bones and joints is a dynamic and complex process, as bone deposition (formation of new bone materials) and resorption (breakdown of the bone matrix to release calcium and phosphorus) are the continuous processes to determine bone balance. Bones are required for locomotion, protection of internal organs, and have endocrine functions to maintain mineral homeostasis. Joints are responsible for resisting mechanical stress/trauma, aiding in locomotion, and supporting the overall musculoskeletal system. Amino acids have multiple regulatory, compositional, metabolic, and functional roles in maintaining the health of bones and joints. Their disorders are prevalent in mammals and significantly reduce the quality of life. These abnormalities in companion animals, specifically cats and dogs, commonly lead to elective euthanasia due to the poor quality of life. Multiple disorders of bones and joints result from genetic predisposition and are heritable, but other factors such as nutrition, growth rate, trauma, and physical activity affect how the disorder manifests. Treatments for cats and dogs are primarily to slow the progression of these disorders and assist in pain management. Therapeutic supplements such as Cosequin and formulated diets rich in amino acids are used commonly as treatments for companion animals to reduce pain and slow the progression of those diseases. Also, amino acids (e.g., taurine, arginine, glycine, proline, and 4-hydroxyproline), and glucosamine reduce inflammation and pain in animals with bone and joint disorders. Gaining insight into how amino acids function in maintaining bone and joint health can aid in developing preventative diets and therapeutic supplementations of amino acids to improve the quality of life in companion animals.

Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1.

Apoptosis occurs during development when a separation of tissues is needed. Synovial joint formation is initiated at the presumptive site (interzone) within a cartilage anlagen, with changes in cellular differentiation leading to cavitation and tissue separation. Apoptosis has been detected in phalangeal joints during development, but its role and regulation have not been defined. Here, we use a mouse model of brachydactyly type A1 (BDA1) with an IhhE95K mutation, to show that a missing middle phalangeal bone is due to the failure of the developing joint to cavitate, associated with reduced apoptosis, and a joint is not formed. We showed an intricate relationship between IHH and interacting partners, CDON and GAS1, in the interzone that regulates apoptosis. We propose a model in which CDON/GAS1 may act as dependence receptors in this context. Normally, the IHH level is low at the center of the interzone, enabling the "ligand-free" CDON/GAS1 to activate cell death for cavitation. In BDA1, a high concentration of IHH suppresses apoptosis. Our findings provided new insights into the role of IHH and CDON in joint formation, with relevance to hedgehog signaling in developmental biology and diseases.

Prepared for landing: A simple activation strategy scales muscle force to landing height.

Before landing from a jump or fall, animals preactivate muscles to stiffen their limb joints but it is unclear how muscles tune limb stiffness and how collision forcefulness is anticipated. We measured electromyography and force from the lateral gastrocnemius muscle during landings in turkeys, an animal model that allows for direct measurements of muscle force. Many studies of landings in humans and other animals have found the duration of muscle preactivation to be constant, starting approximately 100 ms before impact, irrespective of fall duration. Therefore, we hypothesized a lack of relationship between fall duration (as dictated by drop height), muscle activity onset-time, and force at toe-down. Contrary to our expectations, both muscle activity and force rose from briefly after fall initiation until toe-down. Preactivation duration was proportional to fall height, while the rate of force rise was consistent across drop heights, resulting in force at landing and leg stiffness being proportional to fall height. Onset of muscle activity lagged 22 ± 7 ms (mean ± S.E.M.) from fall initiation, consistent with a reflex response initiation of the force ramp-up. Together, our results suggest that a constant (clock-like) rate of motor unit recruitment, initiated at fall initiation provides a preactivation that is proportional to drop height. The result is a tuning of pre-landing muscle force, providing a limb stiffening that is proportional to impact intensity, possibly without using information about fall distance.

Elevated DAS28-ESR in patients with rheumatoid arthritis who have comorbid fibromyalgia is associated more with tender joint counts than with patient global assessment or swollen joint counts: implications for assessment of inflammatory activity.

OBJECTIVES: More than 20% of rheumatoid arthritis (RA) patients have comorbid fibromyalgia (FM+), which may elevate DAS28-ESR (disease activity score 28-erythrocyte sedimentation rate) and other indices, resulting in challenges to assess inflammatory disease activity. Although several reports indicate that elevated patient global assessment (PATGL) may elevate DAS28 in the absence of inflammatory activity, less information is available concerning the other three components, tender joint count (TJC), swollen joint count (SJC), and erythrocyte sedimentation rate (ESR), to possibly elevate DAS28 in FM+ vs. FM- RA patients. METHODS: A PubMed search identified 14 reports which presented comparisons of DAS28-ESR and its four components in RA FM+ vs. FM- groups. Median DAS28, component arithmetic differences, pooled effect sizes and 95% confidence intervals were analysed in the FM+ vs. FM- groups. RESULTS: In FM+ vs. FM- groups, median DAS28 was 5.3 vs. 4.2, SJC 4.0 vs. 3.0, TJC 13.2 vs. 5.3, PATGL 61.6 vs. 39.9, ESR 26.3 vs. 26.5. DAS28-ESR was classified as "high" (>5.1) in 11/14 FM+ groups and "moderate" (3.2-5.1) in all 14 FM- groups. Effect sizes in FM+ vs. FM- groups for DAS28-ESR, SJC, TJC, PATGL, and ESR were large (≥0.8) in 10/14, 1/13, 12/13, 7/13, and 1/13 comparisons, respectively, and pooled effect sizes 0.84 (0.3, 1.4), 0.33 (-0.4, 1.0), 1.27 (0.01, 2.5), 0.91 (-0.6, 2.4), and 0.07 (-0.6, 0.7), respectively. CONCLUSIONS: DAS28-ESR is elevated significantly in FM+ vs. FM- RA patients; pooled effect sizes were highest for TJC, followed by PATGL, SJC and ESR. The findings appear relevant to response and remission criteria, treat-to-target, and general management of RA.

Dihydroartemisinin alleviates erosive bone destruction by modifying local Treg cells in inflamed joints: A novel role in the treatment of rheumatoid arthritis.

Treg cell-based therapy has exhibited promising efficacy in combatting rheumatoid arthritis (RA). Dihydroartemisinin (DHA) exerts broad immunomodulatory effects across various diseases, with its recent spotlight on T-cell regulation in autoimmune conditions. The modulation of DHA on Treg cells and its therapeutic role in RA has yet to be fully elucidated. This study seeks to unveil the influence of DHA on Treg cells in RA and furnish innovative substantiation for the potential of DHA to ameliorate RA. To this end, we initially scrutinized the impact of DHA-modulated Treg cells on osteoclast (OC) formation in vitro using Treg cell-bone marrow-derived monocyte (BMM) coculture systems. Subsequently, employing the collagen-induced arthritis (CIA) rat model, we validated the efficacy of DHA and probed its influence on Treg cells in the spleen and popliteal lymph nodes (PLN). Finally, leveraging deep proteomic analysis with data-independent acquisition (DIA) and parallel accumulation-serial fragmentation (PASEF) technology, we found the alterations in the Treg cell proteome in PLN by proteomic analysis. Our findings indicate that DHA augmented suppressive Treg cells, thereby impeding OC formation in vitro. Consistently, DHA mitigated erosive joint destruction and osteoclastogenesis by replenishing splenic and joint-draining lymph node Treg cells in CIA rats. Notably, DHA induced alterations in the Treg cell proteome in PLN, manifesting distinct upregulation of alloantigen Col2a1 (Type II collagen alfa 1 chain) and CD8a (T-cell surface glycoprotein CD8 alpha chain) in Treg cells, signifying DHA's targeted modulation of Treg cells, rendering them more adept at sustaining immune tolerance and impeding bone erosion. These results unveil a novel facet of DHA in the treatment of RA.

Electromyography-driven musculoskeletal models with time-varying fatigue dynamics improve lumbosacral joint moments during lifting.

Muscle fatigue is prevalent across different aspects of daily life. Tracking muscle fatigue is useful to understand muscle overuse and possible risk of injury leading to musculoskeletal disorders. Current fatigue models are not suitable for real-world settings as they are either validated using simulations or non-functional tasks. Moreover, models that capture the changes to muscle activity due to fatigue either assume a linear relationship between muscle activity and muscle force or utilize a simple muscle model. Personalised electromygraphy (EMG)-driven musculoskeletal models (pEMS) offer person-specific approaches to model muscle and joint kinetics during a wide repertoire of daily life tasks. These models utilize EMG, thus capturing central fatigue-dependent changes in multi-muscle bio-electrical activity. However, the peripheral muscle force decay is missing in these models. Thus, we studied the influence of fatigue on a large scale pEMS of the trunk. Eleven healthy participants performed functional asymmetric lifting task. Average peak body-weight normalized lumbosacral moments (BW-LM) were estimated to be 2.55 ± 0.26 Nm/kg by reference inverse dynamics. After complete exhaustion of the lower back, the pEMS overestimated the peak BW-LM by 0.64 ± 0.37 Nm/kg. Then, we developed a time-varying muscle force decay model resulting in a time-varying pEMS (t-pEMS). This reduced the difference between BW-LM estimated by the t-pEMS and reference to 0.49 ± 0.14 Nm/kg. We also showed that five fatiguing contractions are sufficient to calibrate the t-pEMS. Thus, this study presents a person and muscle specific model to track fatigue during functional tasks.

Evaluation of generic EMG-Torque models across two Upper-Limb joints.

Advanced single-use dynamic EMG-torque models require burdensome subject-specific calibration contractions and have historically been assumed to produce lower error than generic models (i.e., models that are identical across subjects and muscles). To investigate this assumption, we studied generic one degree of freedom (DoF) models derived from the ensemble median of subject-specific models, evaluated across subject, DoF and joint. We used elbow (N = 64) and hand-wrist (N = 9) datasets. Subject-specific elbow models performed statistically better [5.79 ± 1.89 %MVT (maximum voluntary torque) error] than generic elbow models (6.21 ± 1.85 %MVT error). However, there were no statistical differences between subject-specific vs. generic models within each hand-wrist DoF. Next, we evaluated generic models across joints. The best hand-wrist generic model had errors of 6.29 ± 1.85 %MVT when applied to the elbow. The elbow generic model had errors of 7.04 ± 2.29 %MVT when applied to the hand-wrist. The generic elbow model was statistically better in both joints, compared to the generic hand-wrist model. Finally, we tested Butterworth filter models (a simpler generic model), finding no statistical differences between optimum Butterworth and subject-specific models. Overall, generic models simplified EMG-torque training without substantive performance degradation and provided the possibility of transfer learning between joints.

Articular surface interactions distinguish dinosaurian locomotor joint poses.

Our knowledge of vertebrate functional evolution depends on inferences about joint function in extinct taxa. Without rigorous criteria for evaluating joint articulation, however, such analyses risk misleading reconstructions of vertebrate animal motion. Here we propose an approach for synthesizing raycast-based measurements of 3-D articular overlap, symmetry, and congruence into a quantitative "articulation score" for any non-interpenetrating six-degree-of-freedom joint configuration. We apply our methodology to bicondylar hindlimb joints of two extant dinosaurs (guineafowl, emu) and, through comparison with in vivo kinematics, find that locomotor joint poses consistently have high articulation scores. We then exploit this relationship to constrain reconstruction of a pedal walking stride cycle for the extinct dinosaur Deinonychus antirrhopus, demonstrating the utility of our approach. As joint articulation is investigated in more living animals, the framework we establish here can be expanded to accommodate additional joints and clades, facilitating improved understanding of vertebrate animal motion and its evolution.