Fetal Immunomodulatory Environment Following Cartilage Injury-The Key to CARTILAGE Regeneration?

Fetal cartilage fully regenerates following injury, while in adult mammals cartilage injury leads to osteoarthritis (OA). Thus, in this study, we compared the in vivo injury response of fetal and adult ovine articular cartilage histologically and proteomically to identify key factors of fetal regeneration. In addition, we compared the secretome of fetal ovine mesenchymal stem cells (MSCs) in vitro with injured fetal cartilage to identify potential MSC-derived therapeutic factors. Cartilage injury caused massive cellular changes in the synovial membrane, with macrophages dominating the fetal, and neutrophils the adult, synovial cellular infiltrate. Correspondingly, proteomics revealed differential regulation of pro- and anti-inflammatory mediators and growth-factors between adult and fetal joints. Neutrophil-related proteins and acute phase proteins were the two major upregulated protein groups in adult compared to fetal cartilage following injury. In contrast, several immunomodulating proteins and growth factors were expressed significantly higher in the fetus than the adult. Comparison of the in vitro MSCs proteome with the in vivo fetal regenerative signature revealed shared upregulation of 17 proteins, suggesting their therapeutic potential. Biomimicry of the fetal paracrine signature to reprogram macrophages and modulate inflammation could be an important future research direction for developing novel therapeutics.

Course of serum amyloid A (SAA) plasma concentrations in horses undergoing surgery for injuries penetrating synovial structures, an observational clinical study.

BACKGROUND: Injuries penetrating synovial structures are common in equine practice and often result in septic synovitis. Significantly increased plasma levels of serum amyloid A (SAA) have been found in various infectious conditions in horses including wounds and septic arthritis. Plasma SAA levels were found to decrease rapidly once the infectious stimulus was eliminated. The purpose of the current study was to investigate the usefulness of serial measurements of plasma SAA as a monitoring tool for the response to treatment of horses presented with injuries penetrating synovial structures. In the current study plasma SAA concentrations were measured every 48 hours (h) during the course of treatment. RESULTS: A total of 19 horses with a wound penetrating a synovial structure were included in the current study. Horses in Group 1 (n = 12) (injuries older than 24 h) only needed one surgical intervention. Patients in this group had significantly lower median plasma SAA levels (P = 0.001) between 48 h (median 776 mg/L) and 96 h (median 202 mg/L) after surgery. A significant decrease (P = 0.004) in plasma SAA levels was also observed between 96 h after surgery (median 270 mg/L) and 6 days (d) after surgery (median 3 mg/L). Four horses (Group 2) required more than one surgical intervention. In contrast to Group 1 patients in Group 2 had either very high initial plasma concentrations (3378 mg/L), an increase or persistently high concentrations of plasma SAA after the first surgery (median 2525 mg/L). A small group of patients (n = 3) (Group 3) were admitted less than 24 h after sustaining a wound. In this group low SAA values at admission (median 23 mg/L) and peak concentrations at 48 h after surgery (median 1016 mg/L) were observed followed by a decrease in plasma SAA concentration over time. CONCLUSIONS: A decrease in plasma SAA concentrations between two consecutive time points could be associated with positive response to treatment in the current study. Therefore, serial measurements of plasma SAA could potentially be used as an additional inexpensive, quick and easy tool for monitoring the treatment response in otherwise healthy horses presented with injuries penetrating synovial structures. However further studies will be necessary to ascertain its clinical utility.

[Ramp lesions : Tips and tricks in diagnostics and therapy]. / Rampenläsionen : Tipps und Tricks in Diagnostik und Therapie.

There is an increasing biomechanical and anatomical understanding of the different types of meniscal lesions. Lesions of the posterior part of the medial meniscus in the meniscosynovial area have recently received increased attention. They generally occur in association with anterior cruciate ligament (ACL) injuries. They are often missed ("hidden lesions") due to the fact that they cannot be seen by routine anterior arthroscopic inspection. Furthermore, meniscosynovial lesions play a role in anteroposterior knee laxity and, as such, they may be a cause of failure of ACL reconstruction or of postoperative persistent laxity. Little information is available regarding their cause with respect to injury mechanism, natural history, biomechanical implications, healing potential and treatment options. This article presents an overview of the currently available knowledge of these ramp lesions, their possible pathomechanism, classification, biomechanical relevance as well as repair techniques.

[Imaging of the elbow joint with focus MRI. Part 2: muscles, nerves and synovial membranes]. / Bildgebung des Ellenbogengelenks mit Fokus MRT. Teil 2: Muskeln, Nerven und Synovia.

This review article discusses the magnetic resonance imaging (MRI) features and pathological changes of muscles, nerves and the synovial lining of the elbow joint. Typical imaging findings are illustrated and discussed. In addition, the cross-sectional anatomy and anatomical variants, such as accessory muscles and plicae are discussed. Injuries of the muscles surrounding the elbow joint, as well as chronic irritation are particularly common in athletes. Morphological changes in MRI, for example tennis or golfer's elbow are typical and often groundbreaking. By adapting the examination sequences, imaging planes and slices, complete and incomplete tendon ruptures can be reliably diagnosed. Although the clinical and electrophysiological examinations form the basis for the diagnosis of peripheral neuropathies, MRI provides useful additional information about the precise localization due to its high resolution and good soft tissue contrast and helps to rule out differential diagnoses. Synovial diseases, such as inflammatory arthritis, proliferative diseases and also impinging plicae must be considered in the MRI diagnostics of the elbow joint.

Changes of early post-traumatic osteoarthritis in an ovine model of simulated ACL reconstruction are associated with transient acute post-injury synovial inflammation and tissue catabolism.

The study described here tested the hypothesis that early intra-articular inflammation is associated with the development of post-traumatic osteoarthritis (PTOA) in a sheep model. We extended previously published work in which we investigated joint gross morphology and synovial mRNA expression of inflammatory and catabolic molecules 2 weeks after anatomic Anterior cruciate ligament (ACL) autograft reconstructive surgery (ACL-R). The same variables have been analyzed at 20 weeks post surgery together with new experimental variables at both time points. Animals were sacrificed at 20 weeks post ACL-R surgery and their joints graded for signs of PTOA. Synovial samples were harvested for histological grading plus mRNA and protein analysis for a panel of inflammatory and catabolic molecules. The mRNA expression levels for this panel plus connective tissue matrix turnover molecules were also investigated in cartilage samples. Results of gross morphological assessments at 20 weeks post surgery showed some changes consistent with early OA, but indicated little progression of damage from the 2 week time point. While significant alterations in mRNA levels for synovial inflammatory and catabolic molecules were detected at 2 weeks, values had normalized by 20 weeks. Similarly, all mRNA expression levels for inflammatory and catabolic molecules in articular cartilage had returned to normal levels by 20 weeks post ACL-R surgery. We conclude that synovial inflammatory processes are initiated very early after ACL-R surgery and may instigate events that lead to the gross cartilage and joint abnormalities observed as early as 2 weeks. However, the absence of sustained inflammation and joint instability may prevent OA progression.

Cellular apoptosis and proliferation in the middle and late intrasynovial tendon healing periods.

PURPOSE: Cellular apoptosis might be an important molecular event in the middle or late healing periods of intrasynovial tendons, but this has not been studied. We aimed to investigate cellular apoptosis and corresponding cellular proliferation in the middle and late healing stages of intrasynovial tendons. METHODS: The flexor digitorum profundus tendons of 48 long toes (24 chickens) were completely transected within the sheath region and were repaired surgically. At days 28, 42, 56, and 84 after surgery, tendons were harvested and sectioned. In situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to detect apoptotic cells. The sections were stained immunofluorescently with antibodies to proliferating cell nuclear antigen to assess proliferation and to Bcl-2 (an anti-apoptotic protein). Positively stained tenocytes were counted, and their distributional differences were verified in 3-dimensional images. RESULTS: The repaired intrasynovial tendons exhibited generally greater apoptosis in the surface region than in the core. The differences were more remarkable in the extended region than in the junction region of the cut tendon. At the core of the junction site, apoptosis of tenocytes was pronounced at all time points, but it was less severe at the core of the extended region. The proliferating cell nuclear antigen-positive and Bcl-2-positive tenocytes decreased significantly and continually at days 28, 42, and 56, respectively; these tenocytes were at a minimum at days 56 and 84. CONCLUSIONS: Apoptotic changes of tenocytes are most marked in the surface region and in the junction region of the healing tendon in the middle and late healing stages. Apoptosis in the core is less dramatic compared to that in the surface in the extended tendon regions. Cellular proliferation declines drastically and is minimal at days 56 and 84. CLINICAL RELEVANCE: Tenocyte apoptosis in the middle and late stages might be an important event contributing to intrasynovial tendon remodeling, which affects the healing strength and formation of adhesions.

Monocytes, Macrophages, and Their Potential Niches in Synovial Joints - Therapeutic Targets in Post-Traumatic Osteoarthritis?

Synovial joints are complex structures that enable normal locomotion. Following injury, they undergo a series of changes, including a prevalent inflammatory response. This increases the risk for development of osteoarthritis (OA), the most common joint disorder. In healthy joints, macrophages are the predominant immune cells. They regulate bone turnover, constantly scavenge debris from the joint cavity and, together with synovial fibroblasts, form a protective barrier. Macrophages thus work in concert with the non-hematopoietic stroma. In turn, the stroma provides a scaffold as well as molecular signals for macrophage survival and functional imprinting: "a macrophage niche". These intricate cellular interactions are susceptible to perturbations like those induced by joint injury. With this review, we explore how the concepts of local tissue niches apply to synovial joints. We introduce the joint micro-anatomy and cellular players, and discuss their potential interactions in healthy joints, with an emphasis on molecular cues underlying their crosstalk and relevance to joint functionality. We then consider how these interactions are perturbed by joint injury and how they may contribute to OA pathogenesis. We conclude by discussing how understanding these changes might help identify novel therapeutic avenues with the potential of restoring joint function and reducing post-traumatic OA risk.

Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1ß.

Cartilage defects in temporomandibular disorders (TMD) lead to chronic pain and seldom heal. Synovium-derived mesenchymal stem cells (SMSCs) exhibit superior chondrogenesis and have become promising seed cells for cartilage tissue engineering. However, local inflammatory conditions that affect the repair of articular cartilage by SMSCs present a challenge, and the specific mechanism through which the function remains unclear. Thus, it is important to explore the chondrogenesis of SMSCs under inflammatory conditions of TMD such that they can be used more effectively in clinical treatment. In this study, we obtained SMSCs from TMD patients with severe cartilage injuries. In response to stimulation with IL-1ß, which is well known as one of the most prevalent cytokines in TMD, MMP13 expression increased, while that of SOX9, aggrecan, and collagen II decreased during chondrogenic differentiation. At the same time, IL-1ß upregulated the expression of mTOR and decreased the ratio of LC3-II/LC3-I and the formation of autophagosomes. Further study revealed that rapamycin pretreatment promoted the migration of SMSCs and the expression of chondrogenesis-related markers in the presence of IL-1ß by inducing autophagy. 3-Benzyl-5-((2-nitrophenoxy)methyl)-dihydrofuran-2(3H)-one (3BDO), a new activator of mTOR, inhibited autophagy and increased the expression of p-GSK3ßser9 and ß-catenin, simulating the effect of IL-1ß stimulation. Furthermore, rapamycin reduced the expression of mTOR, whereas the promotion of LC3-II/LC3-I was blocked by the GSK3ß inhibitor TWS119. Taken together, these results indicate that rapamycin enhances the chondrogenesis of SMSCs by inducing autophagy, and GSK3ß may be an important regulator in the process of rapamycin-induced autophagy. Thus, inducing autophagy may be a useful approach in the chondrogenic differentiation of SMSCs in the inflammatory microenvironment and may represent a novel TMD treatment.

MRI appearance of the pectinofoveal fold.

OBJECTIVE: The pectinofoveal fold is an intraarticular structure of the hip that has had only limited study in the clinical and anatomic literature. This fold may resemble a hip plica; however, symptomatic hip plicae are now being recognized and treated at hip arthroscopy. We wished to determine the frequency and appearance of the pectinofoveal fold on hip MR arthrography. By defining the variations in its appearance, the normal pectinofoveal fold can be distinguished from pathologic hip plicae. MATERIALS AND METHODS: One hundred fifty-two hip MR arthrography examinations of patients who subsequently underwent hip arthroscopy were retrospectively reviewed. Each MR examination was reviewed for the presence of a pectinofoveal fold. If present, the fold was measured in the anteroposterior, mediolateral, and superior-inferior dimensions; evaluated for smooth or irregular contour; and evaluated for a femoral or capsular site of insertion. RESULTS: The pectinofoveal fold was visualized on hip MR arthrograms in 144 of the 152 (95%) patients and visualized at hip arthroscopy in 150 of the 152 (99%) patients. The average thickness of the fold was 2.6 mm (range, 1-13 mm) in the mediolateral dimension and 17 mm (range, 1-32 mm) in the anteroposterior dimension. The average length of the fold in the superior-inferior dimension was 23.3 mm (range, 7-44 mm). The pectinofoveal fold had a smooth contour in 75 of the 144 (52%) patients with examinations that showed the fold and an irregular contour in 69 of 144 (48%) patients. The fold was found to insert onto the capsule in 108 of 144 (75%) patients and onto the femur in the remaining 36. CONCLUSION: The pectinofoveal fold should almost always be visualized at MR arthrography. The fold can have various appearances and attachment sites, and these normal variations should not be mistaken for fold abnormalities. These findings should be useful in distinguishing this normal structure from normal and pathologic plicae.

A pyogenic, ruptured Baker's cyst induced by arthroscopic pressure pump irrigation.

Post-steroid septic arthritis can be treated with irrigation pump assisted arthroscopic synovectomy. The high-intra-articular fluid pressures can force the pyogenic fluid into a pre-existing Baker's cyst. The cyst can rupture and with the pre-existing steroid induced immune-suppression, the calf abscess will be hard to control. Therefore, thorough investigation with an ultrasound-guided aspiration followed by an early drainage of the collection is warranted and mandatory. Close monitoring for the development of a deep thrombosis of the popliteal vein is required.

Use of positive contrast radiography to identify synovial involvement in horses with traumatic limb wounds.

BACKGROUND: The diagnostic value of positive contrast radiography in the work-up of suspected synovial infection in horses with limb wounds near synovial structures has yet to be systematically evaluated. OBJECTIVES: To determine the specificity, sensitivity and positive and negative predictive values of positive contrast radiography for identification of synovial infection in a population of horses with limb wounds. STUDY DESIGN: Retrospective case study comparing the performance of positive contrast radiography to the gold standard of synovial fluid cytology in horses presenting with limb wounds in the vicinity of synovial structures. METHODS: Case records of horses presenting to the Royal Veterinary College Equine Hospital between 2010 and 2015 with limb wounds that may have compromised adjacent synovial structures were analysed. Synovial fluid cytology results were used to categorise synovial structures in infected and noninfected groups. Positive contrast radiography results were compared between infected and noninfected groups and sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Fifty horses with 66 synovial structures were included in the study. Positive contrast radiography had a high specificity (86.4%), but only a moderate sensitivity (59.1%) for the identification of synovial infection. In addition, a low positive predictive value (68.4%) and high negative predictive value (80.9%) were observed in this population of horses. MAIN LIMITATIONS: Sensitivity, specificity and predictive values may differ between different synovial structures and cases. Different conclusions may be drawn from the results in a single population. Sensitivity and specificity of positive contrast radiography may also be influenced by different techniques used by examiners and by inherent characteristics of individual cases. CONCLUSIONS: Positive contrast radiography should be used for the investigation of potential synovial infection in horses with limb wounds, particularly if no synovial fluid sample for laboratory analysis can be obtained. However, it appears that positive contrast radiography is best used in combination with other tests to ensure that a correct and timely diagnosis is made.

Joint morphogenetic cells in the adult mammalian synovium.

The stem cells that safeguard synovial joints in adulthood are undefined. Studies on mesenchymal stromal/stem cells (MSCs) have mainly focused on bone marrow. Here we show that lineage tracing of Gdf5-expressing joint interzone cells identifies in adult mouse synovium an MSC population largely negative for the skeletal stem cell markers Nestin-GFP, Leptin receptor and Gremlin1. Following cartilage injury, Gdf5-lineage cells underpin synovial hyperplasia through proliferation, are recruited to a Nestin-GFPhigh perivascular population, and contribute to cartilage repair. The transcriptional co-factor Yap is upregulated after injury, and its conditional ablation in Gdf5-lineage cells prevents synovial lining hyperplasia and decreases contribution of Gdf5-lineage cells to cartilage repair. Cultured Gdf5-lineage cells exhibit progenitor activity for stable chondrocytes and are able to self-organize three-dimensionally to form a synovial lining-like layer. Finally, human synovial MSCs transduced with Bmp7 display morphogenetic properties by patterning a joint-like organ in vivo. Our findings further the understanding of the skeletal stem/progenitor cells in adult life.

Indications for Hip Arthroscopy.

CONTEXT: Hip arthroscopy is gaining popularity within the field of orthopaedic surgery. The development and innovation of hip-specific arthroscopic instrumentation and improved techniques has resulted in improved access to the hip joint and ability to treat various hip pathologies. EVIDENCE ACQUISITION: Electronic databases, including PubMed and MEDLINE, were queried for articles relating to hip arthroscopy indications (1930-2017). STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Initially used as a technique for loose body removal, drainage/debridement of septic arthritis, and treatment of pediatric hip disorders, hip arthroscopy is currently used to treat various hip conditions. The recognition of femoroacetabular impingement (FAI) as a source of hip pain in young adults has rapidly expanded hip arthroscopy by applying the principles of osseous correction that were previously described and demonstrated via an open surgical dislocation approach. Hip pathologies can be divided into central compartment, peripheral compartment, peritrochanteric space, and subgluteal space disorders. CONCLUSION: Although hip arthroscopy is a minimally invasive procedure that may offer decreased morbidity, diminished risk of neurovascular injury, and shorter recovery periods compared with traditional open exposures to the hip, it is important to understand the appropriate patient selection and indications.

Running Injuries: The Infrapatellar Fat Pad and Plica Injuries.

When considering knee pain in runners, clinicians differentiate sources of symptoms and determine their cause. Knee problems arise when a runner increases the amount/frequency of the loading through the lower limb. The way the loading is distributed through the knee determines which tissues are abnormally loaded. Knee problems cannot be considered in isolation, requiring a thorough investigation of static and dynamic lower limb mechanics, and footwear and surfaces. This article examines potential sources of knee pain and explores the role of the infrapatellar fat pad and synovial plica in the mechanics of the knee and its involvement in knee symptoms.

Bucket-handle tear of medial plica.

Plicae are synovial folds, classified according to their anatomical relationship to the patella. The medial patellar plica is normally asymptomatic, but it may cause symptoms when it becomes thickened and fibrotic. We describe three cases of bucket-handle tear of the medial patellar plica. They all suffered from anterior knee pain and clicking. Our cases' symptoms began when they incurred twisting injuries to the knee; therefore, we think that they had an asymptomatic plica first. Pain and clicking began because of the bucket-handle portion rubbed over the medial femoral condyle with knee flexion, and they improved after resection of the bucket-handle portion. Consequently, we think that medial patellar plica can be symptomatic not only when it becomes thickened or fibrotic but also when a bucket handle tear occurs.

Microinjury to the synovial membrane may cause disaggregation of proteoglycans in rabbit knee joint articular cartilage.

Proteoglycans (PGs) isolated from articular cartilage (AC) of mature rabbits subjected to two or more consecutive intraarticular (IA) injections of sterile saline 24 h apart showed an aggregation defect in the presence of excess hyaluronic acid (HA). Although the PG contents of experimental and control cartilages were indistinguishable, a higher proportion of PGs were extractable from the 3 X IA tissues, as assessed by uronic acid analysis. Proteoglycans from experimental and control cartilages when examined by Sepharose CL-2B chromatography showed two subunit populations, the smaller (KAV = 0.70) containing more ketatan sulphate than the larger (KAV = 0.31). Cultures of AC from IA joints released more 35SO4-labelled PGs into the media over 72 h than control tissues and consisted mainly of PG degradation products although 20% could aggregate in the presence of HA. Examination of PG aggregation 2 weeks after 2 X IA or 3 X IA injections showed that the defect initiated was still present; however, cartilage of immature rabbits was not affected by the 2 X IA procedure.

Injuries of exercise.

This article presents a brief overview of a few of the conditions that may affect the exercising individual. An accurate diagnosis and a positive attitude toward exercise on the part of the physician is stressed.

Knee arthrography. Evolution and current status.

This article explores arthrography of the knee beginning with a brief historical perspective of conventional knee arthrography and culminating in direct and indirect MR arthrography of the knee. This article discusses the advantages of MR arthrography in the radiologic assessment of the postoperative meniscus, abnormalities of articular cartilage, and synovial-based processes.

Ankle tenography. A therapeutic imaging modality.

Ankle tenography is an easily learned technique for the treatment of tenosynovitis. This article describes the procedure in detail and discusses the indications and contraindications for tenography. The anatomy of the ankle tendons is briefly reviewed. This article familiarizes radiologists with this minimally-invasive therapeutic modality so that they can offer it as an option for their referring physicians, who often have few other choices when it comes to managing patients with chronic ankle pain.

Increased vascular permeability evoked by mechanical trauma and haemarthrosis in synovium of the rat.

Increased vascular permeability was studied in the synovium of the rat's stifle joint following mechanical trauma and haemarthrosis. The abnormal permeability was detected by injecting colloidal carbon intravenously and examining the synovial vessels for intra-mural deposits of carbon. The effects of rotational and stretch injuries were minimal except when accompanied by intra-synovial haemorrhage. Injection of autologous whole blood into the joint evoked a marked venular permeability response which persisted for 24 hours. These findings indicate that the major factor in the formation of traumatic joint effusions is haemorrhage into the articular cavity or the adjacent tissues.