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Objective: Cartilage and meniscus are important structures that maintain the health of the knee joint. Early detection of changes in the internal components of cartilage and meniscus before morphological changes occur is essential to prevent and delay the development of osteoarthritis (OA). This study was designed to determine the changes in the matrix composition of morphologically intact cartilage and meniscus during the acute phase of an anterior cruciate ligament (ACL) rupture, as well as the effect of different states of meniscus (intact or tear) on adjacent cartilage during the acute phase. Methods: This cross‐sectional study compared and analyzed 50 patients in the acute phase of ACL rupture who underwent surgical treatment and 66 age‐, weight‐ and height‐matched healthy volunteers from May 2022 to May 2023 at our institution. Mean T2 relaxation times and effect sizes in different regions of tibiofemoral articular cartilage and meniscus were compared between the two groups using the Mann–Whitney nonparametric t‐test, and correlations between different meniscal states and adjacent cartilage were analyzed. Results: Both in the lateral and medial compartments of the knee, T2 relaxation times were significantly higher in all subregions of cartilage and meniscus in the ACL rupture group (p < 0.05), and the site of injury was predominantly centered in the medial compartment (femur, p = 0.000; tibia, p = 0.000; anterior horn, p = 0.000). In the respective compartments, the posterior horn of the lateral meniscus showed a significant positive correlation with the mid‐cartilage of the femoral and tibial (r = 0.566, p = 0.035; r = 0.611, p = 0.02); and the posterior horn of the medial meniscus showed a significant positive correlation with the posterior tibial cartilage (r = 0.668, p = 0.018). Conclusion: During the acute phase of ACL rupture, the internal composition of the cartilage and meniscus undergoes significant changes, even if the morphology is intact. More importantly, the state of the meniscus significantly affects the internal composition of the adjacent cartilage. This is an early warning sign of OA, which should be closely monitored and carefully managed in clinical practice. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) affects millions of people worldwide, but there are limited drugs available to treat it, so acquiring a more comprehensive comprehension of the underlying reasons and mechanisms behind inflammation is crucial, as well as developing novel therapeutic approaches to manage it and mitigate or forestall associated harm. It is evident that current in vitro models cannot faithfully replicate all aspects of joint diseases, which makes them ineffective as tools for disease research and drug testing. Organ-on-a-chip (OoC) technology is an innovative platform that can mimic the microenvironment and physiological state of living tissues more realistically than traditional methods by simulating the spatial arrangement of cells and interorgan communication. This technology allows for the precise control of fluid flow, nutrient exchange, and the transmission of physicochemical signals, such as bioelectrical, mechanical stimulation and shear force. In addition, the integration of cutting-edge technologies like sensors, 3D printing, and artificial intelligence enhances the capabilities of these models. Here, we delve into OoC models with a particular focus on Synovial Joints-on-a-Chip, where we outline their structure and function, highlighting the potential of the model to advance our understanding of RA. We integrate the actual evidence regarding various OoC models and their possible integration for multisystem disease study in RA research for the first time and introduce the prospects and opportunities of the chip in RA etiology and pathological mechanism research, drug research, disease prevention and human precision medicine. Although many challenges remain, OoC holds great promise as an in vitro model that approaches physiology and dynamics. [ABSTRACT FROM AUTHOR]

The squat and its variants can provide numerous benefits including positively affecting sports performance and injury prevention, injury severity reduction, and rehabilitation. The positive benefits of squat are likely the result of training-induced neural alterations and mechanical and morphological adaptations in tendons, skeletal muscles, and bones, resulting in increased tissue stiffness and cross-sectional area (CSA). Although direct evidence is lacking, structural adaptations can also be expected to occur in ligaments. These adaptations are thought to beneficially increase force transmission and mechanical resistance (e.g., resistance to mechanical strain) and reduce the likelihood and severity of injuries. Adaptations such as these, also likely play an important role in rehabilitation, particularly for injuries that require restricted use or immobilization of body parts and thus lead to a consequential reduction in the CSA and alterations in the mechanical properties of tendons, skeletal muscles, and ligaments. Both volume and particularly intensity (e.g., levels of loading used) of training seem to be important for the mechanical and morphological adaptations for at least skeletal muscles, tendons, and bones. Therefore, the training intensity and volume used for the squat and its variations should progressively become greater while adhering to the concept of periodization and recognized training principles. [ABSTRACT FROM AUTHOR]

Background: In an earlier study, a scaffold-free tissue-engineered construct (TEC) derived from autologous synovial membrane mesenchymal stromal cells (MSCs) was developed and demonstrated to be safe and effective for cartilage repair at 2 years postoperatively. Purpose: To investigate clinical outcomes and magnetic resonance imaging (MRI) findings at 5 years after implantation. Study Design: Case series; Level of evidence, 4. Methods: This was an observational first-in-human study limited to 5 patients (age, 28-46 years) with symptomatic knee chondral lesions (size, 1.5-3.0 cm2) on the medial femoral condyle, lateral femoral condyle, or femoral groove. Synovial MSCs were isolated from arthroscopic biopsy specimens and cultured to develop a TEC that matched the lesion size. The TECs were then implanted into chondral defects without fixation and assessed at up to 5 years postoperatively. The patients were clinically evaluated using the visual analog scale for pain, Lysholm score, Tegner score, and Knee injury and Osteoarthritis Outcome Score. An MRI scan evaluation was also performed for morphologic and compositional quality of the repair tissue at both 2 and 5 years of follow-up. Results: All clinical scores were significantly improved from the preoperative evaluation to the 2- and 5-year follow-ups and the results were stable over time. The MRI scan evaluation showed cartilage defects filled with newly generated tissues with good tissue integration to adjacent host cartilage over time. The cartilage thickness and surface smoothness of the repair cartilage were maintained up to 5 years postoperatively. The MOCART (magnetic resonance observation of cartilage repair tissue) 2.0 Knee Scores remained high at 5 years, although the total points decreased slightly. Conclusion: The results highlight the efficacy and feasibility of autologous scaffold-free TEC derived from synovial MSCs for regenerative cartilage repair via a sutureless and simple implantation procedure, showing good clinical outcomes and MRI findings with stable results at midterm follow-up. Further follow-up will be needed to assess the long-term quality of the repair tissue. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) have gained popularity in recent years as biologic approaches to potentially augment healing after meniscus repair. There have been few studies comparing outcomes in patients undergoing meniscus repair with versus without biologic augmentation and, furthermore, little clarity on the role of biologic augmentation for meniscus repairs performed with concomitant anterior cruciate ligament reconstruction (ACLR). Purpose: To determine the association of BMAC or PRP augmentation with revision surgery after both isolated meniscus repair and meniscus repair performed concomitantly with ACLR. Study Design: Cohort study; Level of evidence, 3. Methods: The PearlDiver Mariner dataset was queried to identify all patients who underwent primary meniscus repair, both with and without concomitant ACLR, and who received ipsilateral BMAC or PRP at the time of surgery. Patients who underwent similar surgery but without BMAC or PRP augmentation were then identified and matched in a 5:1 ratio according to age, sex, body mass index, and various comorbidities to 3 separate BMAC/PRP augmentation groups: overall cohort (with and without ACLR), repair with concomitant ACLR, and isolated repair. The primary outcome was revision meniscus surgery (meniscectomy or revision meniscus repair). Results: Overall, 3420 patients (570 with BMAC/PRP augmentation; 2850 matched controls without augmentation) were included. There were no significant differences in the reported demographics or comorbidities between any of the BMAC/PRP groups and their respective matched controls (P >.05 for all comparisons). There was no difference in revision rate between BMAC/PRP-augmented isolated meniscus repairs and matched controls (P =.235). Patients who underwent BMAC/PRP-augmented meniscus repair with concomitant ACLR experienced a significantly lower incidence of revision surgery compared with matched controls without BMAC/PRP augmentation (5.2% vs 7.9% respectively; odds ratio, 0.41; 95% CI, 0.27-0.63; P <.001), but the number of revisions was relatively small. Conclusion: There was no association between BMAC or PRP augmentation and the incidence of revision surgery after isolated primary meniscus repair. There was a statistically significant decrease in the rate of revision meniscus surgery when BMAC or PRP was used to augment meniscus repairs in the setting of concurrent ACLR; however, the overall revision rates were small. [ABSTRACT FROM AUTHOR]

Treatment of osteoarthritic patients requires the development of morphologically and mechanically complex hyaline cartilage at the injury site. A tissue engineering approach toward differentiating mesenchymal stem cells into articular chondrocytes has been developed to overcome the drawbacks of conventional therapeutic and surgical procedures. To imitate the native micro and macro environment of articular chondrocytes, cell culture parameters such as oxygen concentration, mechanical stress, scaffold design, and growth factor signalling cascade regulation must be addressed. This review aims to illuminate the path toward developing tissue engineering approaches, accommodating these various parameters and the role these parameters play in regulating chondrogenesis for better articular cartilage development to treat osteoarthritis effectively. Osteoarthritis is a common problem where the protective layer of cartilage on the joints wears away. It's difficult to treat with current methods. However, stem cell therapy is a promising alternative that has been researched a lot recently. Stem cells are special cells that can change into different types of tissue, including cartilage. Scientists are trying to figure out how to get these stem cells to grow into cartilage effectively. They are also trying to understand how stem cells find the right place in the body to go and do their job. By modifying the genes of stem cells and using special materials and growth factors, scientists hope to improve the effectiveness of stem cell therapy for osteoarthritis. To pave the way toward effectively treating damaged articular chondrocytes, this article reviews the various cell culture parameters required to develop an efficient tissue engineering protocol for differentiating autologous MSC in cartilaginous tissue. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic degenerative osteoarthropathy. Although it has been revealed that a variety of factors can cause or aggravate the symptoms of OA, the pathogenic mechanisms of OA remain unknown. Reliable OA models that accurately reflect human OA disease are crucial for studies on the pathogenic mechanism of OA and therapeutic drug evaluation. This review first demonstrated the importance of OA models by briefly introducing the OA pathological features and the current limitations in the pathogenesis and treatment of OA. Then, it mainly discusses the development of different OA models, including animal and engineered models, highlighting their advantages and disadvantages from the perspective of pathogenesis and pathology analysis. In particular, the state-of-the-art engineered models and their potential were emphasized, as they may represent the future direction in the development of OA models. Finally, the challenges in obtaining reliable OA models are also discussed, and possible future directions are outlined to shed some light on this area. [ABSTRACT FROM AUTHOR]

The current literature has mainly focused on the biology of tendons and on the characterization of the biological properties of tenocytes and tenoblasts. It is still not understood how these cells can work together in homeostatic equilibrium. We put forward the concept of the "tendon unit" as a morpho-functional unit that can be influenced by a variety of external stimuli such as mechanical stimuli, hormonal influence, or pathological states. We describe how this unit can modify itself to respond to such stimuli. We evidence the capability of the tendon unit of healing itself through the production of collagen following different mechanical stimuli and hypothesize that restoration of the homeostatic balance of the tendon unit should be a therapeutic target. [ABSTRACT FROM AUTHOR]

A characteristic feature of arthritic diseases is cartilage extracellular matrix (ECM) degradation, often orchestrated by the overexpression of matrix metalloproteinases (MMPs) and other proteases. The interplay between fibril level degradation and the tissue-level aggregate response to biomechanical loading was explored in this work by a computational multiscale cartilaginous model. We considered the relative abundance of collagenases (MMP-1) and gelatinases (MMP-9) in surrogate models, where the diffusion (spatial distribution) of these enzymes and the subsequent, co-localized fibrillar damage were spatially randomized with Latin Hypercube Sampling. The computational model was constructed by incorporating the results from prior molecular dynamics simulations (tensile test) of microfibril degradation into a hyper-elastoplastic fibril-reinforced cartilage model. Including MMPs-mediated collagen fibril-level degradation in computational models may help understand the ECM pathomechanics at the tissue level. The mechanics of cartilage tissue and fibril show variations in mechanical integrity depending on the different combinations of MMPs-1 and 9 with a concentration ratio of 1:1, 3:1, and 1:3 in simulated indentation tests. The fibril yield (local failure) was initiated at 20.2 ± 3.0 (%) and at 23.0 ± 2.8 (%) of bulk strain for col 1:gel 3 and col 3: gel 1, respectively. The reduction in failure stress (global response) was 39.8% for col 1:gel 3, 37.5% for col 1:gel 1, and 36.7% for col 3:gel 1 compared with the failure stress of the degradation free tissue. These findings indicate that cartilage's global and local mechanisms of failure largely depend on the relative abundance of the two key enzymes—collagenase (MMP-1) and gelatinase (MMP-9) and the spatial characteristics of diffusion across the layers of the cartilage ECM. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo Zuzhi Gongcheng Yanjiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Currently, there are no effective clinical or experimental treatments to fully restore the function of the torn acetabular labrum. To fill the gap, here, we report the finding of progenitor cells in labral tissue, which can be recruited and stimulated to repair torn acetabular labral tissue. This study aimed to develop a biomolecule releasing bioadhesive which can speed up labral tissue healing by eliciting autologous labral progenitor cellular responses. A click chemistry‐based bioadhesive, capable of releasing biomolecules, was synthesized to exert ~3× adhesion strength compared with fibrin glue. Via the release of platelet‐derived growth factor (PDGF), the adhesive was shown to actively recruit and stimulate the proliferation of labral progenitor cells to the tear sites and within the adhesive. Finally, the ability of this biomolecules‐releasing adhesive designed to promote labral tissue regeneration was evaluated using discarded human acetabular labrum tissue compared with surgical suture ex vivo. Histological analysis shows that PDGF‐releasing bioadhesive yielded significantly more labrum cell responses and extracellular matrix protein (proteoglycan and collagen) production at the tear tissue site than surgical suture controls. The results confirm that the new PDGF‐releasing bioadhesive can activate the responses of autologous labral progenitor cells to significantly improve labral tissue regeneration. Clinical significance: These PDGF‐releasing bioadhesives may serve as a new and effective tool for repairing and regenerating acetabular labrum tears. [ABSTRACT FROM AUTHOR]

Abnormal loading of the knee due to injuries or obesity is thought to contribute to the development of osteoarthritis (OA). Small animal models have been used for studying OA progression mechanisms. However, numerical models to study cartilage responses under dynamic loading in preclinical animal models have not been developed. Here we present a musculoskeletal finite element model of a rat knee joint to evaluate cartilage biomechanical responses during a gait cycle. The rat knee joint geometries were obtained from a 3-D MRI dataset and the boundary conditions regarding loading in the joint were extracted from a musculoskeletal model of the rat hindlimb. The fibril-reinforced poroelastic (FRPE) properties of the rat cartilage were derived from data of mechanical indentation tests. Our numerical results showed the relevance of simulating anatomical and locomotion characteristics in the rat knee joint for estimating tissue responses such as contact pressures, stresses, strains, and fluid pressures. We found that the contact pressure and maximum principal strain were virtually constant in the medial compartment whereas they showed the highest values at the beginning of the gait cycle in the lateral compartment. Furthermore, we found that the maximum principal stress increased during the stance phase of gait, with the greatest values at midstance. We anticipate that our approach serves as a first step towards investigating the effects of gait abnormalities on the adaptation and degeneration of rat knee joint tissues and could be used to evaluate biomechanically-driven mechanisms of the progression of OA as a consequence of joint injury or obesity. Author summary: Osteoarthritis is a disease of the musculoskeletal system which is characterized by the degradation of articular cartilage. Changes in the knee loading after injuries or obesity contribute to the development of cartilage degeneration. Since injured cartilage cannot be reversed back to intact conditions, small animal models have been widely used for investigating osteoarthritis progression mechanisms. Moreover, experimental studies have been complemented with numerical models to overcome inherent limitations such as cost, difficulties to obtain accurate measures and replicate degenerative situations in the knee joint. However, computational models to study articular cartilage responses under dynamic loading in small animal models have not been developed. Thus, here we present a musculoskeletal finite element model (MSFE) of a rat knee joint to evaluate cartilage biomechanical responses during gait. Our computational model considers both the anatomical and locomotion characteristics of the rat knee joint for estimating mechanical responses in the articular cartilage. We suggest that our approach can be used to investigate tissue adaptations based on the mechanobiological responses of the cartilage to prevent the progression of osteoarthritis. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic inflammation after joint injury, ranging from sprains to articular fracture, contributes to the development of arthritis, and the administration of interleukin 1 (IL-1) receptor antagonist (IL-1Ra) is a potential intervention to mitigate this response. Although IL-1Ra mitigates cartilage degenerative changes induced by IL-1, lidocaine is used for local pain management in acute joint injury. Intra-articular delivery of both drugs in combination would be a novel and possibly disease–modifying treatment. However, it is not known whether the interaction with lidocaine at clinical concentrations (1%) would alter the efficacy of IL-1Ra to protect cartilage from the catabolic effects of IL-1. Hypothesis: Treatment of articular cartilage with IL-1Ra in combination with a clinically relevant concentration of lidocaine (1%) will inhibit the catabolic effects of IL-1α in a manner similar to treatment with IL-1Ra alone. Study Design: Controlled laboratory study. Methods: Fresh porcine cartilage explants were harvested, challenged with IL-1α, and incubated for 72 hours with IL-1Ra or a combination of IL-1Ra and lidocaine. The primary outcome was total sulfated glycosaminoglycan (sGAG) release. Additional experiments assessed the effect of storage temperature and premixing of IL-1Ra and lidocaine on sGAG release. All explants were histologically assessed for cartilage degradation using a modified Mankin grading scale. Results: The combination of IL-1Ra and lidocaine, premixed at various time points and stored at room temperature or 4°C, was as effective as IL-1Ra alone at inhibiting IL-1α–mediated sGAG release. Mankin histopathology scores supported these findings. Conclusion: Our hypothesis was supported, and results indicated that the combination of IL-1Ra and lidocaine was as efficacious as IL-1Ra treatment alone in acutely mitigating biological cartilage injury due to IL-1α in an explant model. Clinical Significance: The combination of IL-1Ra and lidocaine is stable when reagents are stored in advance of administration at varying temperatures, providing clinically relevant information about storage of medications. The ability to premix and store this drug combination for intra–articular delivery may provide a novel treatment after joint injury to provide pain relief and block inflammation–induced catabolism of joint tissues. [ABSTRACT FROM AUTHOR]

Formalin‐fixed and paraffin‐embedded (FFPE) biospecimens are a valuable and widely‐available resource for diagnostic and research applications. With biobanks of tissue samples available in many institutions, FFPE tissues could prove to be a valuable resource for translational orthopaedic research. The purpose of this study was to characterize the molecular profiles and degree of histologic degeneration on archival fragments of FFPE human menisci obtained during arthroscopic partial meniscectomy. We used FFPE menisci for multiplexed gene expression analysis using the NanoString nCounter® platform, and for histological assessment using a quantitative scoring system. In total, 17 archival specimens were utilized for integrated histologic and molecular analyses. The median patient age was 22 years (range: 14–62). We found that the genes with the highest normalized counts were those typically expressed in meniscal fibrocartilage. Gene expression differences were identified in patient cohorts based on age (≤40 years), including genes associated with the extracellular matrix and tissue repair. The majority of samples showed mild to moderate histologic degeneration. Based on these data, we conclude that FFPE human menisci can be effectively utilized for molecular evaluation following a storage time as long as 11 years. Statement of Clinical Significance: The integration of histological and transcriptomic analyses described in this study will be useful for future studies investigating the basis for biological classification of meniscus specimens in patients. Further exploration into the genes and pathways uncovered by this study may suggest targets for biomarker discovery and identify patients at greater risk for osteoarthritis once the meniscus is torn. [ABSTRACT FROM AUTHOR]

The objective of the current study was to investigate the feasibility of quantitative 3D ultrashort echo time (UTE)‐based biomarkers in detecting proteoglycan (PG) loss and collagen degradation in human cartilage. A total of 104 cartilage samples were harvested for a trypsin digestion study (n = 44), and a sequential trypsin and collagenase digestion study (n = 60), respectively. Forty‐four cartilage samples were randomly divided into a trypsin digestion group (tryp group) and a control group (phosphate‐buffered saline [PBS] group) (n = 22 for each group) for the trypsin digestion experiment. The remaining 60 cartilage samples were divided equally into four groups (n = 15 for each group) for sequential trypsin and collagenase digestion, including PBS + Tris (incubated in PBS, then Tris buffer solution), PBS + 30 U col (incubated in PBS, then 30 U/ml collagenase [30 U col] with Tris buffer solution), tryp + 30 U col (incubated in trypsin solution, then 30 U/ml collagenase with Tris buffer solution), and tryp + Tris (incubated in trypsin solution, then Tris buffer solution). The 3D UTE‐based MRI biomarkers included T1, multiecho T2*, adiabatic T1ρ (AdiabT1ρ), magnetization transfer ratio (MTR), and modeling of macromolecular proton fraction (MMF). For each cartilage sample, UTE‐based biomarkers (T1, T2*, AdiabT1ρ, MTR, and MMF) and sample weight were evaluated before and after treatment. PG and hydroxyproline assays were performed. Differences between groups and correlations were assessed. All the evaluated biomarkers were able to differentiate between healthy and degenerated cartilage in the trypsin digestion experiment, but only T1 and AdiabT1ρ were significantly correlated with the PG concentration in the digestion solution (p = 0.004 and p = 0.0001, respectively). In the sequential digestion experiment, no significant differences were found for T1 and AdiabT1ρ values between the PBS + Tris and PBS + 30 U col groups (p = 0.627 and p = 0.877, respectively), but T1 and AdiabT1ρ values increased significantly in the tryp + Tris (p = 0.031 and p = 0.024, respectively) and tryp + 30 U col groups (both p < 0.0001). Significant decreases in MMF and MTR were found in the tryp + 30 U col group compared with the PBS + Tris group (p = 0.002 and p = 0.001, respectively). It was concluded that AdiabT1ρ and T1 have the potential for detecting PG loss, while MMF and MTR are promising for the detection of collagen degradation in articular cartilage, which could facilitate earlier, noninvasive diagnosis of osteoarthritis. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a painful and disabling musculoskeletal disorder, with a large impact on the global population, resulting in several limitations on daily activities. In OA, inflammation is frequent and mainly controlled through inflammatory cytokines released by immune cells. These outbalanced inflammatory cytokines cause cartilage extracellular matrix (ECM) degradation and possible growth of neuronal fibers into subchondral bone triggering pain. Even though pain is the major symptom of musculoskeletal diseases, there are still no effective treatments to counteract it and the mechanisms behind these pathologies are not fully understood. Thus, there is an urgent need to establish reliable models for assessing the molecular mechanisms and consequently new therapeutic targets. Models have been established to support this research field by providing reliable tools to replicate the joint tissue in vitro. Studies firstly started with simple 2D culture setups, followed by 3D culture focusing mainly on cell-cell interactions to mimic healthy and inflamed cartilage. Cellular approaches were improved by scaffold-based strategies to enhance cell-matrix interactions as well as contribute to developing mechanically more stable in vitro models. The progression of the cartilage tissue engineering would then profit from the integration of 3D bioprinting technologies as these provide 3D constructs with versatile structural arrangements of the 3D constructs. The upgrade of the available tools with dynamic conditions was then achieved using bioreactors and fluid systems. Finally, the organ-on-a-chip encloses all the state of the art on cartilage tissue engineering by incorporation of different microenvironments, cells and stimuli and pave the way to potentially simulate crucial biological, chemical, and mechanical features of arthritic joint. In this review, we describe the several available tools ranging from simple cartilage pellets to complex organ-on-a-chip platforms, including 3D tissue-engineered constructs and bioprinting tools. Moreover, we provide a fruitful discussion on the possible upgrades to enhance the in vitro systems making them more robust regarding the physiological and pathological modeling of the joint tissue/OA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a progressive, chronic, debilitating autoimmune disease manifested clinically by polyarthralgia associated with joint dysfunction triggering the antibodies targeting against the self-neoepitopes determined by autoimmune responses associated with chronic arthritic attacks. Arthritis is not an inherited disease but caused by stimulation of some hidden arthritis susceptible genes lowering the quality of life throughout the world, particularly in developing countries. RA generally affects the joints like wrists, elbows, knees and ankles. Usually women are more affected by RA than men due to the prevalence of hormonal changes. Age is also an important factor that contributes for the development of RA. Several anti-inflammatory and disease-modifying drugs are available for RA therapy. However, the prolonged use of these drugs is associated with severe side effects. Furthermore, these drugs are effective only in a proportion of RA patients. Hence, there is a need to search for new therapeutic agents that are effective yet safe. Interestingly, a variety of herbs and other natural products offer a vast resource for such anti-arthritic agents. Nature has been a source of medicinal agents for more than thousands of years and herbal therapy predominates in traditional systems of medicine as well as in alternative medicine practiced in various cultures such as Indian system of medicine, Chinese Traditional Medicine, Unani classical literature. This review article presents about various polyherbal formulations (PHF) utilized in RA treatment. PHF has been used all around the earth due to its medicinal and therapeutic application. The present review deals with various commercial and non-commercial polyherbal formulation used by different countries of the world for the treatment of RA, their therapeutic potentials including clinical and preclinical results along with their safety and efficacy. This review will facilitate to gain all about the past scientific research and the necessary information about the anti-arthritic activities of polyherbal formulations which will insist the young researchers for future research to protect human beings from RA and may serves as a natural gold for the promotion of mankind. [ABSTRACT FROM AUTHOR]

Aim: To mimic the ultrastructural morphology of the meniscus with nanofiber scaffolds coupled with controlled growth factor delivery to modulate cellular performance for tissue engineering of menisci. Methods: The authors functionalized collagen nanofibers by conjugating heparin to the following growth factors for sustained release: PDGF-BB, TGF-β1 and CTGF. Results: Incorporating growth factors increased human meniscal and synovial cell viability, proliferation and infiltration in vitro, ex vivo and in vivo; upregulated key genes involved in meniscal extracellular matrix synthesis and enhanced generation of meniscus-like tissue. Conclusion: The authors' results indicate that functionalizing collagen nanofibers can create a cell-favorable micro- and nanoenvironment and can serve as a system for sustained release of bioactive factors. Meniscal tears are a common injury to the part of the knee called the meniscus. Loss of meniscal tissue can lead to arthritis. In this study, the authors aimed to recreate the structure of the human meniscus using very thin (nanometers in diameter) fibers made of collagen. The authors also attached proteins called growth factors to the fibers. The addition of these proteins increased the growth rate of cells collected from human knee tissue. The levels of important genes involved in meniscal tissue formation were increased in these cells. These results show that adding proteins such as growth factors to collagen nanofibers can create an environment beneficial to growing meniscal tissue. Successful development of this technology could help in repairing meniscal damage in people. [ABSTRACT FROM AUTHOR]

Purpose: Tendon overuse injuries are prevalent conditions with limited therapeutic options to halt disease progression. The specialized extracellular matrix (ECM) both enables joint function and mediates mechanical signals to tendon cells, driving biological responses to exercise or injury. With overuse, tendon ECM composition and structure changes at multiple scales, disrupting mechanotransduction and resulting in inadequate repair and disease progression. This review highlights the multiscale ECM changes that occur with tendon overuse and corresponding effects on cell-matrix interactions and cellular response to load.Results: Different functional joint requirements and tendon types experience a wide range of loading profiles, creating varied downstream mechanical stimuli. Distinct ECM structure and mechanical properties within the fascicle matrix, interfascicle matrix, and enthesis and their varied disruption with overuse are considered. The pericellular matrix (PCM) comprising the microscale tendon cell environment has a unique composition that changes with overuse injury and exercise, suggesting an important role in mechanotransduction and promoting repair. Cell-matrix interactions are mediated by structures including cilia, integrins, connexins and cytoskeleton that signal downstream homeostasis, adaptation, or repair. ECM disruption with tendon overuse may cause altered mechanical loading and cell-matrix interactions, resulting in mechanobiological understimulation, apoptosis, and ineffective repair. Current interventions to promote repair of tendon overuse injuries including exercise, targeting cell signaling, and modulating inflammation are considered.Conclusion: Future therapeutics should be assessed with regard of their effects on multiscale mechanotransduction in addition to joint function, with consideration of the central role of ECM. [ABSTRACT FROM AUTHOR]

Excessive pressure or overload induces and aggravates osteoarthritic changes in articular cartilage, but the underlying biomechanical forces are largely ignored in existing pharmacological in vitro models that are used to investigate drugs against osteoarthritis (OA). Here, we introduce a novel in vitro model to perform pathophysiological and pharmacological investigations, in which cartilage explants are subjected to intermittent cyclic pressure, and characterize its ability to mimic OA‐like tissue reactivity. Mechanical loading time‐dependently increased the biosynthesis, content and retention of fibronectin (Fn), whereas collagen metabolism remained unchanged. This protocol upregulated the production and release of proteoglycans (PGs). The release of PGs from explants was significantly inhibited by a matrix metalloproteinase (MMP) inhibitor, suggesting the involvement of such proteinases in the destruction of the model tissue, similar to what is observed in human OA cartilage. In conclusion, the metabolic alterations in our new biomechanical in vitro model are similar to those of early human OA cartilage, and our pharmacological prevalidation with an MMP‐inhibitor supports its value for further in vitro drug studies. [ABSTRACT FROM AUTHOR]

Copyright of Ataturk University Journal of Veterinary Sciences is the property of Ataturk University Coordinatorship of Scientific Journals and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The increasing incidence of anterior cruciate ligament (ACL) and meniscal injuries has led to strong interest in discovering new methods to enhance the biological healing response of these tissues. Platelet-rich plasma (PRP) contains various growth factors associated with a positive healing response, but few existing clinical studies are available to determine the risks and benefits of these therapies. Purpose: To determine the effects of intraoperative PRP on postoperative knee function and complications at 2 years after ACL reconstruction with meniscal repair. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective matched case-control study was conducted between 2013 and 2017 using a single surgeon database of 1014 patients undergoing primary ACL reconstruction with concomitant meniscal repair, resulting in 324 patients (162 PRP patients and 162 control patients) who met the study criteria. Patients were matched by age, sex, graft type, and meniscal injury. The Single Assessment Numeric Evaluation (SANE) was administered at 2 years, and injury surveillance was conducted. Secondary outcomes included the time to return to activity (months), self-reported knee function (International Knee Documentation Committee [IKDC] score), functional performance testing (knee range of motion, single-leg balance, single-leg hopping, agility testing), and postoperative complications (graft failure, infection, loss of motion [requiring repeat arthroscopy for lysis of adhesions], venous thrombosis, etc). Univariate models were used for between-group comparisons, and alpha was set at.05 for all analyses. Results: No differences were found in SANE knee function scores between the PRP and matched-control groups at 2 years (91.6 ± 11.2 vs 92.4 ± 10.6, respectively; P =.599). Additionally, no differences were reported between groups for self-reported function (IKDC score, 87.6 ± 13.3 vs 88.1 ± 12.6; P =.952), functional performance testing (P >.05), and timing of return to activity (7.8 ± 1.9 vs 8.0 ± 1.9 months; P =.765). The PRP group demonstrated a higher rate of postoperative knee motion loss compared with the control group (13.6% vs 4.6%; P <.001). No other differences were observed in postoperative complications (P >.05). Conclusion: The added use of intraoperative PRP did not improve self-reported knee function, functional performance, and timing of return to activity for patients undergoing ACL reconstruction with meniscal repair. Furthermore, the use of PRP may have negative consequences for regaining knee range of motion after surgery. On the basis of these data, surgeons should cautiously consider the application of PRP when planning surgery for intra-articular injuries of the knee. Registration: NCT03704376 (ClinicalTrials.gov identifier). [ABSTRACT FROM AUTHOR]

Osteoarthritis is a common chronic disease of joints characterized by degenerative changes of articular cartilage. An early diagnosis of osteoarthritis may be possible when imaging excised tissue for research in situ at the cellular-molecular scale. Whereas cartilage histopathology is destructive, time-consuming, and limited to 2D views, contrast-enhanced x-ray microscopy (XRM) can image articular cartilage and subchondral bone in 3D. This study evaluates articular cartilage structure ex vivo using both techniques. Osteochondral plugs were excised from non-diseased bovine knees and stained in phosphotungstic acid for 0 to 32 h. XRM imaging revealed an optimal staining time of 16 h and a saturated staining time of 24 h. Histology sections were cut and analyzed by polarized light microscopy (PLM) and second-harmonic-generation dual-photon (SHG-DP) microscopy. Histology photomicrographs were aligned with matching XRM slices and evaluated for features relevant in histopathological scoring of osteoarthritis cartilage, including the tidemark, collagen architecture and chondrocyte morphology. The cartilage collagen network and chondrocytes from the 3D contrast-enhanced XRM were correlated with the 2D histology. This technique has two distinct advantages over routine histopathology: (1) the avoidance of dehydration, demineralization, and deformation of histological sectioning, thereby preserving the intact articular cartilage and subchondral bone plate ex vivo, and (2) the ability to evaluate the entire osteochondral volume in 3D. This work explores several diagnostic features of imaging cartilage, including: visualization of the tidemark in XRM and SHG-DP microscopy, validating the morphology of chondrocytes and nuclei with XRM, SHG-DP and PLM, and correlating collagen birefringence with XRM image intensity. [ABSTRACT FROM AUTHOR]

Background: Different tendons are chosen for anterior cruciate ligament (ACL) reconstruction based on perceived advantages and disadvantages, yet there is a relative paucity of information regarding biologic responsiveness of commonly used tendon grafts to mechanical strain. Purpose: To evaluate the in vitro responses of graft fibroblasts derived from tendons used for ACL reconstruction to clinically relevant strain levels. Study Design: Controlled laboratory study. Methods: Twelve quadriceps tendons (QTs), 12 patellar tendons (PTs), and 9 hamstring tendons (HTs) were harvested from skeletally mature dogs (n = 16). Tendon fibroblasts were isolated and seeded onto BioFlex plates (1 × 105 cells/well). Cells were subjected to 3 strain conditions (stress deprivation, 0%; physiologic, 4%; high, 10%) for 5 days. Media were collected for proinflammatory and metabolic assays. RNA was extracted for gene expression analysis using real-time reverse transcription polymerase chain reaction. Results: Stress deprivation elicited significantly higher metabolic activity from HT and PT cells than from QT cells (P <.001 and P =.001, respectively). There were no differences in metabolic activity among all 3 graft fibroblasts at physiologic and high strain. COL-1 expression was significantly higher in PT versus HT during physiologic strain (P =.007). No significant differences with COL-3 expression were seen. TIMP-1 (P =.01) expression was higher in PT versus HT under physiologic strain. Scleraxis expression was higher in PT versus HT (P =.007) under physiologic strain. A strain-dependent increase in PGE2 levels occurred for all grafts. At physiologic strain conditions, HT produced significantly higher levels of PGE2 versus QT (P <.001) and PT (P =.005). Conclusion: Fibroblasts from common ACL graft tissues exhibited different metabolic responses to mechanical strain. On the basis of these data, we conclude that early production of extracellular matrix and proinflammatory responses from ACL grafts are dependent on mechanical loading and graft source. Clinical Relevance: Graft-specific differences in ACL reconstruction outcomes are known to exist. Our results suggest that there are differences in the biologic responsiveness of cells from the tendon grafts used in ACL reconstruction, which are dependent on strain levels and graft source. The biologic properties of the tissue used for ACL reconstruction should be considered when selecting graft source. [ABSTRACT FROM AUTHOR]

Degeneration is a hallmark of painful joint disease and is mediated by many proteases that degrade joint tissues, including collagenases. We hypothesized that purified bacterial collagenase would initiate nociceptive cascades in the joint by degrading the capsular ligament's matrix and activating innervating pain fibers. Intra-articular collagenase in the rat facet joint was investigated for its effects on behavioral sensitivity, joint degeneration, and nociceptive pathways in the peripheral and central nervous systems. In parallel, a co-culture collagen gel model of the ligament was used to evaluate effects of collagenase on microscale changes to the collagen fibers and embedded neurons. Collagenase induced sensitivity within one day, lasting for 3 weeks (p < 0.001) but did not alter ligament structure, cartilage health, or chondrocyte homeostasis. Yet, nociceptive mediators were increased in the periphery (substance P, pERK, and MMP-1; p ≤ 0.039) and spinal cord (substance P and MMP-1; p ≤ 0.041). The collagen loss (p = 0.008) induced by exposing co-cultures to collagenase was accompanied by altered neuronal activity (p = 0.002) and elevated neuronal MMP-1 (p < 0.001), suggesting microscale collagen degradation mediates sensitivity in vivo. The induction of sustained sensitivity and nociception without joint damage may explain the clinical disconnect in which symptomatic joint pain patients present without radiographic evidence of joint destruction. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is characterized by irreversible cartilage degradation with very limited therapeutic interventions. Drug candidates targeted at prototypic players had limited success until now and systems based approaches might be necessary. Consequently, drug evaluation platforms should consider the biological complexity looking beyond well-known contributors of OA. In this study an ex vivo model of cartilage degradation, combined with measuring releases of 27 proteins, was utilized to study 9 drug candidates. After an initial single drug evaluation step the 3 most promising compounds were selected and employed in an exhaustive combinatorial experiment. The resulting most and least promising treatment candidates were selected and validated in an independent study. This included estimation of mechanical properties via finite element modelling (FEM) and quantification of cartilage degradation as glycosaminoglycan (GAG) release. The most promising candidate showed increase of Young's modulus, decrease of hydraulic permeability and decrease of GAG release. The least promising candidate exhibited the opposite behaviour. The study shows the potential of a novel drug evaluation platform in identifying treatments that might reduce cartilage degradation. It also demonstrates the promise of exhaustive combination experiments and a connection between chondrocyte responses at the molecular level with changes of biomechanical properties at the tissue level. [ABSTRACT FROM AUTHOR]

Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is typically managed in late stages by replacement of the articular cartilage surface with a prosthesis as an effective, though undesirable outcome. As an alternative, hydrogel implants or growth factor treatments are currently of great interest in the tissue engineering community, and scaffold materials are often designed to emulate the mechanical and chemical composition of mature extracellular matrix (ECM) tissue. However, scaffolds frequently fail to capture the structure and organization of cartilage. Additionally, many current scaffold designs do not mimic processes by which structurally sound cartilage is formed during musculoskeletal development. The objective of this review is to highlight methods that investigate cartilage ontogenesis with native and model systems in the context of regenerative medicine. Specific emphasis is placed on the use of cartilage explant cultures that provide a physiologically relevant microenvironment to study tissue assembly and development. Ex vivo cartilage has proven to be a cost-effective and accessible model system that allows researchers to control the culture conditions and stimuli and perform proteomics and imaging studies that are not easily possible using in vivo experiments, while preserving native cell–matrix interactions. We anticipate our review will promote a developmental biology approach using explanted tissues to guide cartilage tissue engineering and inform new treatment methods for OA and joint damage. [ABSTRACT FROM AUTHOR]

Purpose/Aim: Knee meniscus is a wedge-shaped fibrocartilaginous tissue, playing important roles in maintaining joint stability and function. Injuries to the meniscus, particularly with the avascular inner third zone, hardly heal and frequently progress into structural breakdown, followed by the initiation of osteoarthritis. As the importance of meniscus in joint function and diseases is being recognized, the field of meniscus research is growing. Not only development, biology, and metabolism but also injury, repair, and healing of meniscus are being actively investigated. As meniscus functions as an integrated unit of a knee joint, in vivo models with various species have been the predominant method for studying meniscus pathophysiology and for testing healing/regeneration strategies. However, in vivo models for meniscus studies suffer from low reproducibility and high cost. To complement the limitations of in vivo animal models, several types of meniscus explants have been applied as highly controlled, standardized in vitro models to investigate meniscus metabolism, pathophysiology, and repair or regeneration process. This review summarizes and compares the existing meniscus explant models. We also discuss the advantages and disadvantages of each explant model. Conclusion: Despite few outstanding challenges, meniscus explant models have potential to serve as an effective tool for investigations of meniscus metabolism, injury, repair and healing. [ABSTRACT FROM AUTHOR]

The diagnosis of osteoarthritis (OA) currently depends on the presence of pain and radiographic imaging findings, which generally do not present until later stages of the disease when the condition is difficult to treat. Therefore, earlier detection of OA pathology is needed for improved disease management. Ex vivo cartilage studies indicate that changes in the mechanical function of cartilage occur as degeneration progresses during OA. Thus, measurement of the in vivo cartilage mechanical response may serve as an earlier indicator of OA pathology. Though mechanical characterization is classically performed during loading, the unloading (recovery) response of cartilage may also enable determination of mechanical response. Therefore, the purpose of this study was to validate the use of the recovery response for mechanical characterization of cartilage in a controlled, ex vivo environment. To do so, confined compression creep and recovery tests were conducted on cartilage explants (N = 10), and the resulting mechanical properties from both the creep and recovery phases were compared. No statistically significant differences were found in the mechanical properties between the two phases, reinforcing the hypothesis that unloading (recovery) may be a good surrogate for loading. [ABSTRACT FROM AUTHOR]

It has great guiding significance for the prevention of osteoarthritis and the mechanical state of cartilage after tissue engineering repair to study the relationship between the mechanical properties of cartilage and its structure. This paper considered both the consideration of the solid phase, liquid phase, fiber-reinforced phase in the cartilage and the influence of the contents of major fibers and minor fibers near the cartilage surface. Based on these, a tangential zone of cartilage was established, and a certain improvement and optimization of the fiber-reinforced porous elastic model was performed. The Abaqus software and the Fortran language were used to complete simulation. Simulation results were compared with experiment's results to verify the validity of the model. Finally, the model was used to perform finite element analysis of different degrees of repairable depth under sliding conditions. Several results were obtained. When the indenter is farther from the interface at the repair site, the mechanical changes in the cartilage are relatively stable. The contact stress of the tangential layer repair and the full-layer repair is small. The volume fraction of the liquid phase in the tangential layer and the full layer repair is lower than that in the other layer regions. The liquid flow rate and the Von Mises stress at the junction of the tangential layer repair are very high. Simulation results were used to explore differences in cartilage mechanical properties of different repairable depths, so as to select the best repairable depth for cartilage. [ABSTRACT FROM AUTHOR]

The meniscus functions as a load distributor and secondary stabilizer in the knee, and the loss of the meniscus increases the risk of osteoarthritis. Freeze‐thawed menisci are used in clinical practice to replace defective menisci; however, the disadvantages of freeze‐thawed tissues include disease transmission and immune rejection. In this study, we decellularized menisci using high hydrostatic pressure (HHP) and compared the decellularized menisci with freeze‐thawed menisci. Porcine menisci were either pressurized at 1,000 MPa for 10 min and then washed with DNase solution or frozen at −80°C for 2 days and thawed. These menisci then underwent in vitro histological, biochemical, and biomechanical comparisons with native menisci. The HHP‐treated and freeze‐thawed menisci were also subcutaneously implanted in a pig, and later harvested for histological analysis. The numbers of histologically detected cells were significantly lower and the amount of biochemically detected DNA was approximately 100‐fold lower in HHP‐treated than in native and freeze‐thawed menisci. The compression strength of the HHP‐decellularized menisci was decreased after 1 and 50 cycles at 20% strain but was unchanged in the freeze‐thawed menisci. After implantation, the numbers of multinucleated giant cells were significantly lower around the HHP‐treated menisci than around the freeze‐thawed menisci. Recellularization of the HHP‐decellularized menisci was confirmed. Thus, although the HHP‐decellularized menisci were mechanically inferior to the freeze‐thawed meniscus in vitro, they were immunologically superior. Our study is the first to demonstrate the use of HHP for decellularization of the meniscus. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2466–2475, 2019 [ABSTRACT FROM AUTHOR]

The pathophysiology of osteoarthritis (OA) involves dysregulation of anabolic and catabolic processes associated with a broad panel of proteins that ultimately lead to cartilage degradation. An increased understanding about these protein interactions with systematic in vitro analyses may give new ideas regarding candidates for treatment of OA related cartilage degradation. Therefore, an ex vivo tissue model of cartilage degradation was established by culturing tissue explants with bacterial collagenase II. Responses of healthy and degrading cartilage were analyzed through protein abundance in tissue supernatant with a 26-multiplex protein profiling assay, after exposing the samples to a panel of 55 protein stimulations present in synovial joints of OA patients. Multivariate data analysis including exhaustive pairwise variable subset selection identified the most outstanding changes in measured protein secretions. MMP9 response to stimulation was outstandingly low in degrading cartilage and there were several protein pairs like IFNG and MMP9 that can be used for successful discrimination between degrading and healthy samples. The discovered changes in protein responses seem promising for accurate detection of degrading cartilage. The ex vivo model seems interesting for drug discovery projects related to cartilage degradation, for example when trying to uncover the unknown interactions between secreted proteins in healthy and degrading tissues. [ABSTRACT FROM AUTHOR]

Inadequate migration and invasion of the trophoblast cells during embryo implantation is one of the reasons for pregnancy-related complications such as intrauterine growth restriction and preeclampsia. In the present study, relevance of WNT ligands and integrins associated with hepatocyte growth factor (HGF)-mediated migration of HTR-8/SVneo trophoblastic cells has been investigated. Treatment of HTR-8/SVneo cells with HGF led to a dose-dependent increase in their migration. RT-PCR studies revealed a significant increase in the transcripts of WNT4, WNT11, ITGA2, and ITGAV, which was further confirmed at protein level by Western blotting. HGF treatment also led to increased expression of integrin α2β1 and αVβ5 in HTR-8/SVneo cells. Silencing of WNT4, WNT11, ITGA2, and ITGAV by siRNA led to a significant decrease in HGF-mediated migration of cells. Treatment of cells with HGF led to activation of mitogen-activated protein kinases (MAPK) and protein kinase A (PKA) signaling pathways. Inhibition of MAPK/PKA, by selective inhibitors, led to decrease in the expression of above WNT ligands and integrins. Silencing of WNT4/WNT11 led to concomitant decrease in the expression of ITGA2 and ITGAV and vice versa. HGF treatment also led to significant increase in β-catenin expression, a downstream target of both WNT ligands and integrins. Silencing of β-catenin led to decrease in HGF-mediated migration. β-catenin expression was also down-regulated in WNT4/WNT11/ITGA2/ITGAV silenced cells suggesting a possible cross-communication of WNT ligands and integrins via β-catenin. These studies have established the significance of WNT4/WNT11 as well as ITGA2/ITGAV during HGF-mediated migration of HTR-8/SVneo trophoblastic cells. [ABSTRACT FROM AUTHOR]

Our objective was to determine the relationship of T1rho and T2 relaxation mapping to the biochemical and biomechanical properties of articular cartilage through selective digestion of proteoglycans and collagens. Femoral condyles were harvested from porcine knee joints and treated with either chondroitinase ABC (cABC) followed by collagenase, or collagenase followed by cABC. Magnetic resonance images were acquired and cartilage explants were harvested for biochemical, biomechanical, and histological analyses before and after each digestion. Targeted enzymatic digestion of proteoglycans with cABC resulted in elevated T1rho relaxation times and decreased sulfated glycosaminoglycan content without affecting T2 relaxation times. In contrast, extractable collagen and T2 relaxation times were increased by collagenase digestion; however, neither was altered by cABC digestion. Aggregate modulus decreased with digestion of both components. Overall, we found that targeted digestion of proteoglycans and collagens had varying effects on biochemical, biomechanical, and imaging properties. T2 relaxation times were altered with changes in extractable collagen, but not changes in proteoglycan. However, T1rho relaxation times were altered with proteoglycan loss, which may also coincide with collagen disruption. Since it is unclear which matrix components are disrupted first in osteoarthritis, both markers may be important for tracking disease progression. [ABSTRACT FROM AUTHOR]

Hypoxia (low O2) is a ubiquitous microenvironmental factor promoting cancer progression, metastasis, and mortality, owing to the ability of cancer cells to co-opt physiological angiogenic responses. Notwithstanding, the pathophysiological induction of angiogenesis results in an abnormal tumor vasculature, further aggravating hypoxia in a feedforward loop that limits the efficacy of molecular targeted therapies. Recent studies suggest that, besides their canonical roles, angiogenic factors promote a panoply of immunosuppressive effects in the tumor microenvironment. Therefore, intratumoral hypoxia emerges as a hitherto unrecognized mechanism evolutionarily repurposing angiogenic molecules as (patho)physiological immunomodulators. On the other hand, antiangiogenic therapies could be aimed at impeding both tumor growth and immunotolerance toward cancer cells, a beneficial effect that can be countered if hypoxia signaling pathways are left unchecked, leading to therapeutic failure. This review summarizes evidence supporting the hypothesis that hypoxia acts as a common pathophysiological mechanism of resistance to immunotherapeutic and antiangiogenic agents while proposing potential strategies to curtail resistance and mortality in patients bearing solid malignancies. [ABSTRACT FROM AUTHOR]

Elastic fibers provide reversible elasticity to the large arteries and are assembled during development when hemodynamic forces are increasing. Mutations in elastic fiber genes are associated with cardiovascular disease. Mice lacking expression of the elastic fiber genes elastin (Eln-/-), fibulin-4 (Efemp2-/-), or lysyl oxidase (Lox-/-) die at birth with severe cardiovascular malformations. All three genetic knockout models have elastic fiber defects, aortic wall thickening, and arterial tortuosity. However, Eln-/- mice develop arterial stenoses, while Efemp2-/- and Lox-/- mice develop ascending aortic aneurysms. We performed comparative gene array analyses of these three genetic models for two vascular locations and developmental stages to determine differentially expressed genes and pathways that may explain the common and divergent phenotypes. We first examined arterial morphology and wall structure in newborn mice to confirm that the lack of elastin, fibulin-4, or lysyl oxidase expression provided the expected phenotypes. We then compared gene expression levels for each genetic model by three-way ANOVA for genotype, vascular location, and developmental stage. We found three genes upregulated by genotype in all three models, Col8a1, Igfbp2, and Thbs1, indicative of a common response to severe elastic fiber defects in developing mouse aorta. Genes that are differentially regulated by vascular location or developmental stage in all three models suggest mechanisms for location or stagespecific disease pathology. Comparison of signaling pathways enriched in all three models shows upregulation of integrins and matrix proteins involved in early wound healing, but not of mature matrix molecules such as elastic fiber proteins or fibrillar collagens. [ABSTRACT FROM AUTHOR]

The crucial role of the menisci in function and biomechanics of the knee has been increasingly recognized and well described during the past several years. Meniscectomy was a gold standard treatment for a torn meniscus. Reviewing the literature, shows that this procedure is deleterious for the chondral surface. In the last decades, orthopaedic surgeons give a battle to salvaging and repair a torn meniscus, when this is possible. Clinical studies have shown that the introduction of biological augmentation techniques has the potential to enhance meniscus repair especially in young active individuals. Fibrin clot is relative quick to reproduce and easy to use technique which promises encouraging results in repairing the torn meniscus and in the same time is considered one of the most cost effective solutions comparing with others. In this paper our aim is to present the surgical technique of preparation and use of the fibrin clot form autologous blood step-by-step in case series of 24 patients. However, despite the relative ease preparation of fibrin clot from autologous blood, the placement and stabilizing it into the gap of the meniscal rupture arthroscopically is challenging. [ABSTRACT FROM AUTHOR]

Dishevelled (Dvl)-2 represents one of the cytoplasmic proteins, which serves as a pivotal hub in signaling intermediates through a number of different signaling pathways associated with the Wnt family. The aim of the present study was to investigate the roles and mechanisms of Dvl-2 on synovial fibroblasts (SFBs) in osteoarthritis (OA). A Cell Counting kit-8 (CCK-8) assay was used to determine cell viability. An alkaline phosphatase (ALP) test kit was used to measure the activity of ALP. Western blot and reverse transcription-quantitative polymerase chain reaction analysis were used to evaluate the protein and mRNA expression, respectively. The results suggest that depletion of Dvl-2 significantly decreased the expression of osteoprotegerin (OPG) and ALP (P<0.05) and significantly increased the expression of receptor activator of nuclear factor-κB ligand (RANKL), ALP, osteonectin (ON), osteocalcin (OCN) and osterix (P<0.05). In addition, the depletion of Dvl-2 also significantly inhibited the expression of runt-related transcription factor 2 (Runx-2) and β-catenin in SFBs (P<0.05). The effect of Dvl-2 over-expression was opposite to the effect of Dvl-2 silencing. The inactivation of Wnt3a reversed the effect of Dvl-2 silencing. In conclusion, the results indicate that Dvl-2 regulated osteogenic differentiation of SFBs in OA. [ABSTRACT FROM AUTHOR]

Background: Pathogenesis of inflammatory diseases can be tracked by studying the causality relationships among the factors contributing to its development. We could, for instance, hypothesize on the connections of the pathogenesis outcomes to the observed conditions. And to prove such causal hypotheses we would need to have the full understanding of the causal relationships, and we would have to provide all the necessary evidences to support our claims. In practice, however, we might not possess all the background knowledge on the causality relationships, and we might be unable to collect all the evidence to prove our hypotheses. Results: In this work we propose a methodology for the translation of biological knowledge on causality relationships of biological processes and their effects on conditions to a computational framework for hypothesis testing. The methodology consists of two main points: hypothesis graph construction from the formalization of the background knowledge on causality relationships, and confidence measurement in a causality hypothesis as a normalized weighted path computation in the hypothesis graph. In this framework, we can simulate collection of evidences and assess confidence in a causality hypothesis by measuring it proportionally to the amount of available knowledge and collected evidences. Conclusions: We evaluate our methodology on a hypothesis graph that represents both contributing factors which may cause cartilage degradation and the factors which might be caused by the cartilage degradation during osteoarthritis. Hypothesis graph construction has proven to be robust to the addition of potentially contradictory information on the simultaneously positive and negative effects. The obtained confidence measures for the specific causality hypotheses have been validated by our domain experts, and, correspond closely to their subjective assessments of confidences in investigated hypotheses. Overall, our methodology for a shared hypothesis testing framework exhibits important properties that researchers will find useful in literature review for their experimental studies, planning and prioritizing evidence collection acquisition procedures, and testing their hypotheses with different depths of knowledge on causal dependencies of biological processes and their effects on the observed conditions. [ABSTRACT FROM AUTHOR]

The role of heparin as an anticoagulant is well defined; however, its role in tumorigenesis and tumor progression is not clear yet. Some studies have shown that anticoagulant treatment in cancer patients improve overall survival, however, recent clinical trials have not shown a survival benefit in cancer patients receiving heparin treatment. In our previous studies we have shown the inhibitory effects of heparin on Hepatocyte Growth Factor (HGF)-induced invasion and migration in hepatocellular carcinoma (HCC) cells. In this study, we showed the differential effects of heparin on the behaviors of HCC cells based on the presence or absence of HGF. In the absence of HGF, heparin activated HGF/c-Met signaling and promoted motility and invasion in HCC cells. Heparin treatment led to c-Met receptor dimerization and activated c-Met signaling in an HGF independent manner. Heparin-induced c-Met activation increased migration and invasion through ERK1/2, early growth response factor 1 (EGR1) and Matrix Metalloproteinases (MMP) axis. Interestingly, heparin modestly decreased the proliferation of HCC cells by inhibiting activatory phosphorylation of Akt. The inhibition of c-Met signaling reversed heparin-induced increase in motility and invasion and, proliferation inhibition. Our study provides a new perspective into the role of heparin on c-Met signaling in HCC. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Harran University Medical Faculty / Harran Üniversitesi Tıp Fakültesi Dergisi is the property of Harran University Medical Faculty and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cartilage is considered a biphasic material in which the solid is composed of proteoglycans and collagen. In biphasic tissue, the hydraulic pressure is believed to bear most of the load under higher strain rates and its dissipation due to fluid flow determines creep and relaxation behavior. In equilibrium, hydraulic pressure is zero and load bearing is transferred to the solid matrix. The viscoelasticity of the collagen network also contributes to its time-dependent behavior, and the osmotic pressure to load bearing in equilibrium. The aim of the present study was to determine the relative contributions of hydraulic pressure, viscoelastic collagen stress, solid matrix stiffness and osmotic pressure to load carriage in cartilage under transient and equilibrium conditions. Unconfined compression experiments were simulated using a fibril-reinforced poroviscoelastic model of articular cartilage, including water, fibrillar viscoelastic collagen and non-fibrillar charged glycosaminoglycans. The relative contributions of hydraulic and osmotic pressures and stresses in the fibrillar and non-fibrillar network were evaluated in the superficial, middle and deep zone of cartilage under five different strain rates and after relaxation. Initially upon loading, the hydraulic pressure carried most of the load in all three zones. The osmotic swelling pressure carried most of the equilibrium load. In the surface zone, where the fibers were loaded in tension, the collagen network carried 20 % of the load for all strain rates. The importance of these fibers was illustrated by artificially modifying the fiber architecture, which reduced the overall stiffness of cartilage in all conditions. In conclusion, although hydraulic pressure dominates the transient behavior during cartilage loading, due to its viscoelastic nature the superficial zone collagen fibers carry a substantial part of the load under transient conditions. This becomes increasingly important with higher strain rates. The interesting and striking new insight from this study suggests that under equilibrium conditions, the swelling pressure generated by the combination of proteoglycans and collagen reinforcement accounts cartilage stiffness for more than 90 % of the loads carried by articular cartilage. This finding is different from the common thought that load is transferred from fluid to solid and is carried by the aggregate modulus of the solid. Rather, it is transformed from hydraulic to osmotic swelling pressure. These results show the importance of considering both (viscoelastic) collagen fibers as well as swelling pressure in studies of the (transient) mechanical behavior of cartilage. [ABSTRACT FROM AUTHOR]

ABSTRACT Concentrations of pro- and anti-inflammatory cytokines in synovial fluid samples collected from patients with chronic meniscal tears were investigated. An acute inflammatory response is generally reported 24-48 h after knee injury, but the largest body of data available in literature concerns anterior cruciate ligament injury and very little information is available about the balance of soluble factors in the synovial fluid of knees with chronic meniscal tears. Sixty-nine patients (46 males and 23 females) with meniscal tear that occurred more than 3 months earlier were enrolled. According to cartilage integrity assessment by arthroscopic examination, patients were assigned to one of the following groups: (i) no chondral damage ( n = 18); (ii) chondral damage graded from I to II ( n = 15); and (iii) chondral damage graded from III to IV ( n = 37). In all groups, levels of IL-10 and inflammatory cytokines IL-6, TNF-α, and IL-8 where greater compared with those reported in the intact population; by contrast, levels of IL-1ra and IL-1β were significantly lower. Interestingly, IL-6 levels were higher in female than male patients. Cytokine levels did not correlate with degree of chondral damage. IL-6 and IL-1ra levels positively correlated with IL-1β, and negatively correlated with TNF-α. Interestingly, levels of IL-1β and TNF-α were inversely correlated. Our data demonstrate increased levels of pro-inflammatory cytokines (IL-6, IL-8, and TNF-α) in the chronic phase of meniscal trauma. This pro-inflammatory state is maintained in the joint from the time of initial injury to several months later and could be a key factor in hampering cartilage regeneration. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:340-346, 2017. [ABSTRACT FROM AUTHOR]