Drug Targeting and Nanotherapeutic Advancement in the Treatment of Rheumatoid Arthritis: Recent Progress in Drug Delivery Systems.

Pain and swelling in the joints, increased synovial thickness, and bone and cartilage degeneration are all symptoms of Rheumatoid Arthritis (RA). Anti-rheumatic medications, which are used in conventional treatment plans for RA, need high doses, frequent administration, and long-term use, all of which increase the risk of major adverse effects and low patient compliance. Drug Delivery Systems (DDS) have been developed for RA treatment in an effort to avoid these obstacles and improve clinical efficacy. There have been many successful experimental RA models using these techniques. There has been a notable uptick in the study of RA nanotherapies as a prospective improvement over conventional systemic therapy. In order to overcome the limits of traditional treatments, researchers have begun looking into nanotherapeutic approaches, notably drug-delivery nanosystems. The precise delivery and concentration of therapeutic drugs in the affected regions are made possible by the passive or active targeting of systemic administration. Several new DDS for treating RA have been addressed here. Therefore, nanoscale drug delivery devices increase drug solubility and bioavailability while decreasing the need for higher doses.

A Review on Pyrazole Derivatives Used in the Treatment of Rheumatoid Arthritis: Recent Advancement and Drug Development.

Rheumatoid arthritis (RA) is an autoimmune disorder where inflammation and destruc-tion of bone are the hallmarks of the disease. This review focuses on the etiology, pathophysiolo-gy, and treatment strategies for RA, along with the different approaches used for the synthesis of pyrazoles, the characterization of various properties, and their biological significance for curing RA. The activated immune system of the body causes inflammation of the synovial joint due to the interaction of immune cells, such as T and B lymphocytes, macrophages, plasma cells, den-dritic cells and mast cells. The treatment for RA has been revolutionized with the discovery of new chemical compounds and an understanding of their mechanism in the treatment of the dis-ease. Pyrazoles are the starting materials for the synthesis of heterocyclic compounds and possess great relevance in the pharmaceutical field for the development of new drugs. They are versatile bio-scaffolds in medicinal chemistry and organic synthesis. This has been followed by a deep analysis of pyrazoles and their derivatives on the basis of medical significance in the treatment of RA. This follow-up and information may help the chemists, scientists, and researchers to generate new pyrazole compounds with high efficacy for better treatment of patients with RA. We summa-rize the review with an understanding of the core of pyrazoles and a claim that their derivatives may be helpful in the development of efficient drugs against RA.

Evaluation of tendon and ligament microstructure and mechanical properties in a canine model of mucopolysaccharidosis I.

Mucopolysaccharidosis (MPS) I is a lysosomal storage disorder characterized by deficient alpha-l-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a strong clinical need for improved treatment approaches that specifically target joint tissues; however, their development is hampered by poor understanding of underlying disease pathophysiology, including how pathological changes to component tissues contribute to overall joint dysfunction. Ligaments and tendons, in particular, have received very little attention, despite the critical roles of these tissues in joint stability and biomechanical function. The goal of this study was to leverage the naturally canine model to undertake functional and structural assessments of the anterior (cranial) cruciate ligament (CCL) and Achilles tendon in MPS I. Tissues were obtained postmortem from 12-month-old MPS I and control dogs and tested to failure in uniaxial tension. Both CCLs and Achilles tendons from MPS I animals exhibited significantly lower stiffness and failure properties compared to those from healthy controls. Histological examination revealed multiple pathological abnormalities, including collagen fiber disorganization, increased cellularity and vascularity, and elevated GAG content in both tissues. Clinically, animals exhibited mobility deficits, including abnormal gait, which was associated with hyperextensibility of the stifle and hock joints. These findings demonstrate that pathological changes to both ligaments and tendons contribute to abnormal joint function in MPS I, and suggest that effective clinical management of joint disease in patients should incorporate treatments targeting these tissues.

Value of ultrasound-guided synovial biopsy for the diagnosis of infectious arthritis.

Objectives: To determine the value of ultrasound (US)-guided synovial biopsy for the diagnosis of infectious arthritis that could not be detected by other modalities. Material and methods: This descriptive study was conducted among 37 patients with arthritis (3 with shoulder arthritis, 2 with elbow arthritis, 7 with wrist arthritis, 15 with hip arthritis, 4 with knee arthritis, and 5 with ankle arthritis) who underwent US-guided synovial biopsy at Hanoi Medical University Hospital for the diagnosis of infec-tious arthritis that could not be detected by infection laboratory tests, imaging, and/or joint fluid culture. The results of US-guided synovial biopsy were positive for infectious arthritis when those of pathologi-cal analyses, bacterial cultures, and/or polymerase chain reaction test for tuberculosis were positive. The final diagnosis established when the patients were discharged from the hospital was compared with the US-guided synovial biopsy results to calculate the sensitivity and specificity for the diagnosis of infectious arthritis. Results: The median age of the patients was 60 years (range: 22-79 years), and two thirds were women. Infectious arthritis was determined as the final diagnosis in 18 patients. There was no significant difference in the infection laboratory test results, synovial thickness, or magnetic resonance imaging features apart from soft tissue abscess between the infectious and non-infectious arthritis groups (P > 0.05). The US-guided synovial biopsy results were positive in 17 patients. Compared with the sensitivity and specificity of the final diagnosis, those of the US-guided synovial biopsy results for the diagnosis of infectious arthritis were 94.4% and 100%, respectively. The Numerical Rating Scale score was ≤3 in most patients. There were neither vascular nor neurologic complications among the patients. Conclusion: Imaging features and laboratory test results are non-specific for infectious arthritis. US-guided synovial biopsy is a well-tolerated, safe method that has a high value for the diagnosis of infectious arthritis. This modality should then be recommended for patients with unclassified arthritis.

Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage critical for chondrocyte identity.

Osteoarthritis is a degenerative joint disease that causes pain, degradation, and dysfunction. Excessive canonical Wnt signaling in osteoarthritis contributes to chondrocyte phenotypic instability and loss of cartilage homeostasis; however, the regulatory niche is unknown. Using the temporomandibular joint as a model in multiple species, we identify Lgr5-expressing secretory cells as forming a Wnt inhibitory niche that instruct Wnt-inactive chondroprogenitors to form the nascent synovial joint and regulate chondrocyte lineage and identity. Lgr5 ablation or suppression during joint development, aging, or osteoarthritis results in depletion of Wnt-inactive chondroprogenitors and a surge of Wnt-activated, phenotypically unstable chondrocytes with osteoblast-like properties. We recapitulate the cartilage niche and create StemJEL, an injectable hydrogel therapy combining hyaluronic acid and sclerostin. Local delivery of StemJEL to post-traumatic osteoarthritic jaw and knee joints in rabbit, rat, and mini-pig models restores cartilage homeostasis, chondrocyte identity, and joint function. We provide proof of principal that StemJEL preserves the chondrocyte niche and alleviates osteoarthritis.

Dose-dependent effects of enzyme replacement therapy on skeletal disease progression in mucopolysaccharidosis VII dogs.

Mucopolysaccharidosis (MPS) VII is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme ß-glucuronidase. Skeletal abnormalities are common in patients and result in diminished quality of life. Enzyme replacement therapy (ERT) for MPS VII using recombinant human ß-glucuronidase (vestronidase alfa) was recently approved for use in patients; however, to date there have been no studies evaluating therapeutic efficacy in a large animal model of MPS VII. The objective of this study was to establish the effects of intravenous ERT, administered at either the standard clinical dose (4 mg/kg) or a high dose (20 mg/kg), on skeletal disease progression in MPS VII using the naturally occurring canine model. Untreated MPS VII animals exhibited progressive synovial joint and vertebral bone disease and were no longer ambulatory by age 6 months. Standard-dose ERT-treated animals exhibited modest attenuation of joint disease, but by age 6 months were no longer ambulatory. High-dose ERT-treated animals exhibited marked attenuation of joint disease, and all were still ambulatory by age 6 months. Vertebral bone disease was recalcitrant to ERT irrespective of dose. Overall, our findings indicate that ERT administered at higher doses results in significantly improved skeletal disease outcomes in MPS VII dogs.

Morphological and radiological study of the shoulder and elbow joints of the giant anteater (Myrmecophaga tridactyla).

The giant anteater (Myrmecophaga tridactyla) has specialized thoracic limbs to forage by breaking the walls of anthills and termite mounds. They also play critical roles in defense posture and locomotion. This study aimed to provide a morphological and radiographic description of the shoulder joint and elbow joint of the giant anteater. Both joints of 13 tamanduas were assessed by morphological dissections and histological evaluation and radiographies without and with positive contrast. The radiographic projections selected to this study were the mediolateral and craniocaudal projections. The radiographic and anatomical findings were compared with the following results: the shoulder joint had a continuous joint capsule with the tendon sheaths of the short head and long head of the biceps brachii muscle, which could be visualized with an injection of 3 ml of intra-articular contrast. The shoulder joint arthrography was performed with the needle positioned cranially to the joint for contrast injection. The elbow joint presented three articular compartments, and the insertion of the joint capsule was proximal to the radial fossa and distal to the radial tuberosity in the radial notch of the ulna, which were possible to identify with 2 ml of intra-articular contrast. The elbow joint arthrography was performed with the needle positioned laterally to the joint for contrast injection. Moreover, the joint capsule presented a caudomedial distention and fat pads. The powerful muscles of the forelimb play a fundamental role in maintaining the shoulder joint and elbow joint stability due to bony adaptations and the absence of usual ligaments. The morphological and radiological study provided relevant information on the soft-tissue characteristics of shoulder and elbow joints, which may aid clinical-surgical and diagnostic imaging procedures.

The Usefulness of Synovial Fluid Proteome Analysis in Orthopaedics: Focus on Osteoarthritis and Periprosthetic Joint Infections.

Synovial fluid (SF) is a viscous and mucinous substance produced by the synovium, a specialized connective tissue that lines diarthrodial joints. SF represents a source of disease-related proteins that could be used as potential biomarkers in several articular diseases. Based on these findings the study of SF has been gaining increasing importance, in recent years. This review aims to summarize the usefulness of synovial fluid in orthopaedics research and clinical practice, mainly focusing on osteoarthritis (OA) and periprosthetic joint infections (PJIs). Proteomics of the SF has shown the up-regulation of several components of the classic complement pathway in OA samples, including C1, C2, C3, C4A, C4B, C5, and C4 C4BPA, thus depicting that complement is involved in the pathogenesis of OA. Moreover, proteomics has demonstrated that some pro-inflammatory cytokines, namely IL-6, IL-8, and IL-18, have a role in OA. Several SF proteins have been studied to improve the diagnosis of PJIs, including alpha-defensin (Alpha-D), leukocyte esterase (LE), c-reactive protein (CRP), interleukin-6 (IL-6), calprotectin and presepsin. The limits and potentials of these SF biomarkers will be discussed.

Local mechanical stimuli correlate with tissue growth in axolotl salamander joint morphogenesis.

Movement-induced forces are critical to correct joint formation, but it is unclear how cells sense and respond to these mechanical cues. To study the role of mechanical stimuli in the shaping of the joint, we combined experiments on regenerating axolotl (Ambystoma mexicanum) forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a transient receptor potential vanilloid 4 (TRPV4) agonist during joint morphogenesis. We quantified growth and shape in regrown humeri from whole-mount light sheet fluorescence images of the regenerated limbs. Results revealed significant differences in morphology and cell proliferation between groups, indicating that TRPV4 desensitization has an effect on joint shape. To link TRPV4 desensitization with impaired mechanosensitivity, we developed a finite element model of a regenerating humerus. Local tissue growth was the sum of a biological contribution proportional to chondrocyte density, which was constant, and a mechanical contribution proportional to fluid pressure. Computational predictions of growth agreed with experimental outcomes of joint shape, suggesting that interstitial pressure driven from cyclic mechanical stimuli promotes local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.

Synovial joint cavitation initiates with microcavities in interzone and is coupled to skeletal flexion and elongation in developing mouse embryo limbs.

The synovial cavity and its fluid are essential for joint function and lubrication, but their developmental biology remains largely obscure. Here, we analyzed E12.5 to E18.5 mouse embryo hindlimbs and discovered that cavitation initiates around E15.0 with emergence of multiple, discrete, µm-wide tissue discontinuities we term microcavities in interzone, evolving into a single joint-wide cavity within 12 h in knees and within 72-84 h in interphalangeal joints. The microcavities were circumscribed by cells as revealed by mTmG imaging and exhibited a carbohydrate and protein content based on infrared spectral imaging at micro and nanoscale. Accounting for differing cavitation kinetics, we found that the growing femur and tibia anlagen progressively flexed at the knee over time, with peak angulation around E15.5 exactly when the full knee cavity consolidated; however, interphalangeal joint geometry changed minimally over time. Indeed, cavitating knee interzone cells were elongated along the flexion angle axis and displayed oblong nuclei, but these traits were marginal in interphalangeal cells. Conditional Gdf5Cre-driven ablation of Has2 - responsible for production of the joint fluid component hyaluronic acid (HA) - delayed the cavitation process. Our data reveal that cavitation is a stepwise process, brought about by sequential action of microcavities, skeletal flexion and elongation, and HA accumulation. This article has an associated First Person interview with the first author of the paper.

Dcx expression defines a subpopulation of Gdf5 + cells with chondrogenic potentials in E12.5 mouse embryonic limbs.

Growth differentiation factor 5 (Gdf5) and doublecortin (Dcx) genes are both expressed in joint interzone cells during synovial joint development. In this study, we re-analyzed the single cell RNA-sequencing data (Gene Expression Omnibus GSE151985) generated from Gdf5 + cells of mouse knee joints at embryonic stages of E12.5, E13.5, E14.5, and E15.5, with a new focus on Dcx. We found that Dcx expression was enriched in clusters of Gdf5 + cells, with high expression levels of pro-chondrogenic genes including sex determining region Y-box transcription factor 5 (Sox5), Sox6, Sox9, Gdf5, versican, matrilin 4, collagen type II α 1 chain (Col2a1), Col9a1, Col9a2, and Col9a3 at E12.5. Dcx + and Dcx - cells had differential gene expression profiles. The up-regulated genes in Dcx + vs. Dcx - cells at E12.5 and E13.5 were enriched in chondrocyte differentiation and cartilage development, whereas those genes up-regulated at E14.5 and E15.5 were enriched in RNA splicing, protein stability, cell proliferation, and cell growth. Gene expression profiles in Dcx + cells showed rapid daily changes from E12.5 to E15.5, with limited number of genes shared across the time period. Expression of Gdf5, Sox5, Sox6, melanoma inhibitory activity, noggin, odd-skipped related transcription factor 2, matrilin 4, and versican was positively correlated with Dcx expression. Our results demonstrate that Dcx expression defines a subpopulation of Gdf5 + cells with chondrogenic potentials in E12.5 mouse embryonic limbs.

Kinetics of Gene Expression Changes in Equine Fetal Interzone and Anlagen Cells Over 14 Days of Induced Chondrogenesis.

Within developing synovial joints, interzone and anlagen cells progress through divergent chondrogenic pathways to generate stable articular cartilage and transient hypertrophic anlagen cartilage, respectively. Understanding the comparative cell biology between interzone and anlagen cells may provide novel insights into emergent cell-based therapies to support articular cartilage regeneration. The aim of this study was to assess the kinetics of gene expression profiles in these skeletal cell lines after inducing chondrogenesis in culture. Interzone and anlagen cells from seven equine fetuses were isolated and grown in a TGF-ß1 chondrogenic inductive medium. Total RNA was isolated at ten time points (0, 1.5, 3, 6, 12, 24, 48, 96, 168, and 336 h), and gene expression for 93 targeted gene loci was measured in a microfluidic RT-qPCR system. Differential transcriptional responses were observed as early as 1.5 h after the initiation of chondrogenesis. Genes with functional annotations that include transcription regulation responded to the chondrogenic stimulation earlier (1.5-96 h) than genes involved in signal transduction (1.5-336 h) and the extracellular matrix biology (3-336 h). Between interzone and anlagen cell cultures, expression levels of 73 out of the 93 targeted genes were not initially different at 0 h, but 47 out of the 73 genes became differentially expressed under the chondrogenic stimulation. While interzone and anlagen cells are both chondrogenic, they display clear differences in response to the same TGF-ß1 chondrogenic stimulation. This study provides new molecular insight into a timed sequence of the divergent developmental fates of interzone and anlagen cells in culture over 14 days.

Role of Photobiomodulation Therapy in Modulating Oxidative Stress in Temporomandibular Disorders. A Systematic Review and Meta-Analysis of Human Randomised Controlled Trials.

This systematic review and meta-analysis (PROSPERO registration; ref CRD 42020198921) aimed to govern photobiomodulation therapy (PBMT) efficacy in temporomandibular disorder (TMD). PRISMA guidelines and Cochrane Collaboration recommendations were followed. Differences in pain reduction assessment by qualitative measurement with visual analogue scale pain (VAS), pressure threshold (PPT) and maximum mouth opening (MMO) were calculated with 95% confidence intervals and pooled in a random effects model with a subgroup analysis, evaluating the role of follow-up duration. Heterogeneity was analysed using Q and I2 tests. Publication bias was assessed by visual examination of funnel plot symmetry. Qualitative analysis revealed 46% of the 44 included studies showed a high risk of bias. Meta-analysis on 32 out of 44 studies revealed statistically significant intergroup differences (SSID) for VAS (SMD = -0.55; 95% CI = -0.82 to -0.27; Z = 3.90 (p < 0.001)), PPT (SMD = -0.45; 95% CI = -0.89 to 0.00; Z = 1.97 (p = 0.05)) and MMO (SMD = -0.45; 95% CI = -0.89 to 0.00; Z = 1.97 (p = 0.05)), favouring PBMT compared to control treatment strategies. Sensitivity analysis revealed SSID (SMD = -0.53; 95% CI = -0.73 to -0.32; Z = 5.02 (p < 0.0001)) with low heterogeneity (Τ2 = 0.02; χ2 = 16.03 (p = 0.31); I2 = 13%). Hence, this review, for first time, proposed suggested recommendations for PBMT protocols and methodology for future extensive TMD research.

Exploring the lubrication mechanisms of synovial fluids for joint longevity - A perspective.

Synovial fluids are complex fluids responsible for the exceptional lubrication present in synovial joints. These fluids consist of various constituents, including hyaluronic acid, surface-active proteins (i.e., lubricin), surface-active phospholipids, as well as various other proteins such as human serum albumin and γ -globulin seric proteins, each of them playing an essential role in lubrication. Being the key to the most efficient biotribological systems, this article is intended to review the current understanding of the underlying lubrication mechanisms of the synovial fluids enables prospective usage in numerous applications, especially as a lubricant for hip and knee prosthetics in combatting osteoarthritis. Current research focuses on the determination of the role of proteins in prosthetic lubrication, optimal material combinations for prosthesis, and the effects of relevant physical variables in prosthetic lubrication. The characterization of prosthetic lubrication and wear mechanisms by synovial fluids represents a prominent challenge in tribological research, yet also an important hurdle to overcome towards optimal lubrication of articular prosthetics.

Hox11 expression characterizes developing zeugopod synovial joints and is coupled to postnatal articular cartilage morphogenesis into functional zones in mice.

Previous studies on mouse embryo limbs have established that interzone mesenchymal progenitor cells emerging at each prescribed joint site give rise to joint tissues over fetal time. These incipient tissues undergo structural maturation and morphogenesis postnatally, but underlying mechanisms of regulation remain unknown. Hox11 genes dictate overall zeugopod musculoskeletal patterning and skeletal element identities during development. Here we asked where these master regulators are expressed in developing limb joints and whether they are maintained during postnatal zeugopod joint morphogenesis. We found that Hoxa11 was predominantly expressed and restricted to incipient wrist and ankle joints in E13.5 mouse embryos, and became apparent in medial and central regions of knees by E14.5, though remaining continuously dormant in elbow joints. Closer examination revealed that Hoxa11 initially characterized interzone and neighboring cells and was then restricted to nascent articular cartilage, intra joint ligaments and structures such as meniscal horns over prenatal time. Postnatally, articular cartilage progresses from a nondescript cell-rich, matrix-poor tissue to a highly structured, thick, zonal and mechanically competent tissue with chondrocyte columns over time, most evident at sites such as the tibial plateau. Indeed, Hox11 expression (primarily Hoxa11) was intimately coupled to such morphogenetic processes and, in particular, to the topographical rearrangement of chondrocytes into columns within the intermediate and deep zones of tibial plateau that normally endures maximal mechanical loads. Revealingly, these expression patterns were maintained even at 6 months of age. In sum, our data indicate that Hox11 genes remain engaged well beyond embryonic synovial joint patterning and are specifically tied to postnatal articular cartilage morphogenesis into a zonal and resilient tissue. The data demonstrate that Hox11 genes characterize adult, terminally differentiated, articular chondrocytes and maintain region-specificity established in the embryo.

Quantifying the tolerance of chick hip joint development to temporary paralysis and the potential for recovery.

BACKGROUND: Abnormal fetal movements are implicated in joint pathologies such as arthrogryposis and developmental dysplasia of the hip (DDH). Experimentally induced paralysis disrupts joint cavitation and morphogenesis leading to postnatal abnormalities. However, the developmental window(s) most sensitive to immobility-and therefore the best time for intervention-have never been identified. Here, we systematically vary the timing and duration of paralysis during early chick hip joint development. We then test whether external manipulation of immobilized limbs can mitigate the effects of immobility. RESULTS: Timing of paralysis affected the level of disruption to joints, with paralysis periods between embryonic days 4 and 7 most detrimental. Longer paralysis periods produced greater disruption in terms of failed cavitation and abnormal femoral and acetabular geometry. External manipulation of an immobilized limb led to more normal morphogenesis and cavitation compared to un-manipulated limbs. CONCLUSIONS: Temporary paralysis is detrimental to joint development, particularly during days 4 to 7. Developmental processes in the very early stages of joint development may be critical to DDH, arthrogryposis, and other joint pathologies. The developing limb has the potential to recover from periods of immobility, and external manipulation provides an innovative avenue for prevention and treatment of developmental joint pathologies.

Immunomodulatory effects of berberine on the inflamed joint reveal new therapeutic targets for rheumatoid arthritis management.

Rheumatoid arthritis (RA) is a chronic inflammatory syndrome designated by synovial joint inflammation leading to cartilage degradation and bone damage as well as progressive disability. Synovial inflammation is promoted through the infiltration of mononuclear immune cells, dominated by CD4+ T cells, macrophages and dendritic cells (DCs), together with fibroblast-like synoviocytes (FLS), into the synovial compartment. Berberine is a bioactive isoquinoline alkaloid compound showing various pharmacological properties that are mainly attributed to immunomodulatory and anti-inflammatory effects. Several lines of experimental study have recently investigated the therapeutic potential of berberine and its underlying mechanisms in treating RA condition. The present review aimed to clarify determinant cellular and molecular targets of berberine in RA and found that berberine through modulating several signalling pathways involved in the joint inflammation, including PI3K/Akt, Wnt1/ß-catenin, AMPK/lipogenesis and LPA/LPA1 /ERK/p38 MAPK can inhibit inflammatory proliferation of FLS cells, suppress DC activation and modulate Th17/Treg balance and thus prevent cartilage and bone destruction. Importantly, these molecular targets may explore new therapeutic targets for RA treatment.

A single cell transcriptional atlas of early synovial joint development.

Synovial joint development begins with the formation of the interzone, a region of condensed mesenchymal cells at the site of the prospective joint. Recently, lineage-tracing strategies have revealed that Gdf5-lineage cells native to and from outside the interzone contribute to most, if not all, of the major joint components. However, there is limited knowledge of the specific transcriptional and signaling programs that regulate interzone formation and fate diversification of synovial joint constituents. To address this, we have performed single cell RNA-Seq analysis of 7329 synovial joint progenitor cells from the developing murine knee joint from E12.5 to E15.5. By using a combination of computational analytics, in situ hybridization and in vitro characterization of prospectively isolated populations, we have identified the transcriptional profiles of the major developmental paths for joint progenitors. Our freely available single cell transcriptional atlas will serve as a resource for the community to uncover transcriptional programs and cell interactions that regulate synovial joint development.

Effects of Immobilization and Re-Mobilization on Knee Joint Arthrokinematic Motion Quality.

BACKGROUND: Knee immobilization is a common intervention for patients with traumatic injuries. However, it usually leads to biomechanical/morphological disturbances of articular tissues. These changes may contribute to declining kinetic friction-related quality of arthrokinematics; however, this phenomenon has not been analyzed in vivo and remains unrecognized. Thus, the aim of the present study is to investigate the effect of immobilization and subsequent re-mobilization on the quality of arthrokinematics within the patellofemoral joint, analyzed by vibroarthrography (VAG). METHODS: Thirty-four patients after 6-weeks of knee immobilization and 37 controls were analyzed. The (VAG) signals were collected during knee flexion/extension using an accelerometer. Patients were tested on the first and last day of the 2-week rehabilitation program. RESULTS: Immobilized knees were characterized by significantly higher values of all VAG parameters when compared to controls (p < 0.001) on the first day. After 2 weeks, the participants in the rehabilitation program that had immobilized knees showed significant improvement in all measurements compared to the baseline condition, p < 0.05. However, patients did not return to normal VAG parameters compared to controls. CONCLUSION: Immobilization-related changes within the knee cause impairments of arthrokinematic function reflected in VAG signal patterns. The alterations in joint motion after 6 weeks of immobilization may be partially reversible; however, the 2-week physiotherapy program is not sufficient for full recovery.

The iliosacral joint in lizards: an osteological and histological analysis.

The development of the iliosacral joint (ISJ) in tetrapods represented a crucial step in the evolution of terrestrial locomotion. This structure is responsible for transferring forces between the vertebral column and appendicular skeleton, thus supporting the bodyweight on land. However, most research dealing with the water-to-land transition and biomechanical studies in general has focused exclusively on the articulation between the pelvic girdle and femur. Our knowledge about the contact between the pelvic girdle and vertebral column (i.e. the ISJ) at a tissue level is restricted so far to human anatomy, with little to no information available on other tetrapods. This lack of data limits our understanding of the development and evolution of such a key structure, and thus on the pattern and processes of the evolution of terrestrial locomotion. Therefore, we investigated the macro- and microanatomy of the ISJ in limb-bearing squamates that, similar to most non-mammalian, non-avian tetrapods, possess only two sacral ribs articulating with the posterior process of the ilium. Using a combination of osteology, micro-computed tomography and histology, we collected data on the ISJ apparatus of numerous specimens, sampling different taxa and different ontogenetic stages. Osteologically, we recorded consistent variability in all three processes of the ilium (preacetabular, supracetabular and posterior) and sacral ribs that correlate with posture and locomotion. The presence of a cavity between the ilium and sacral ribs, abundant articular cartilage and fibrocartilage, and a surrounding membrane of dense fibrous connective tissue allowed us to define this contact as a synovial joint. By comparison, the two sacral ribs are connected to each other mostly by dense fibrous tissue, with some cartilage found more distally along the margins of the two ribs, defining this joint as a combination of a syndesmosis and synchondrosis. Considering the intermediary position of the ISJ between the axial and appendicular skeletons, the shape of the articular surfaces of the sacral ribs and ilium, and the characteristics of the muscles associated with this structure, we argue that the mobility of the ISJ is primarily driven by the movements of the hindlimb during locomotion. We hypothesize that limited torsion of the ilium at the ISJ happens when the hip is abducted, and the joint is likely able to absorb the compressional and extensional forces related to the protraction and retraction of the femur. The mix of fibres and cartilage between the two sacral ribs instead serves primarily as a shock absorber, with the potential for limited vertical translation during locomotion.