Articular Erosion Research Articles

Microvesicles Released by Osteoclastic Cells Exhibited Chondrogenic, Osteogenic, and Anti-Inflammatory Activities: An Evaluation of the Feasibility of Their Use for Treatment of Osteoarthritis in a Mouse Model

Extracellular vesicles (EVs), particularly exosomes (EXOs) of various skeletal and stem cells, were shown to delay osteoarthritis (OA) progression, and apoptotic bodies (ABs), another EV subtype, of osteoclasts showed osteoanabolic actions and were involved in the osteoclastic-regulation of local bone formation. Moreover, this study demonstrates that microvesicles (MVs) released by osteoclasts displayed potent pro-chondrogenic, pro-osteogenic, and anti-inflammatory activities. These activities were unique to osteoclastic MVs and were not shared by osteoclastic ABs and EXOs or MVs of other cell types. Because chronic synovial inflammation, progressive articular cartilage erosion, abnormal subchondral bone remodeling, and inability to regenerate articular cartilage are key etiologies of OA, we postulate that the foregoing activities of osteoclastic MVs could simultaneously target multiple etiologies of OA and could thereby be an effective therapy for OA. Accordingly, this study sought to assess the feasibility of an osteoclastic MV-based strategy for OA with a mouse tibial plateau injury model of OA. Briefly, tibial plateau injuries were created on the right knees of adult C57BL/6J mice, MVs were intraarticularly injected into the injured joints biweekly, and the OA progression was monitored histologically at five weeks post-injury. The MV treatment reduced the OA-induced losses of articular cartilage area and thickness, decreased irregularity in the articular cartilage surface, reduced loss of gliding/intermediate zone of articular cartilage, reduced osteophyte formation, suppressed synovial inflammation, and decreased the OARSI OA score. In summary, treatment with osteoclastic MVs delayed or reversed OA progression. Thus, this study supports the feasibility of an osteoclastic MV-based therapy for OA.

Development of a Controllable Intelligent Drug Delivery System for Efficient Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a complex inflammatory disease of the joints, which is often accompanied by degeneration of articular cartilage and bone erosion, seriously affecting the quality of life and psychological state of patients. RA is difficult to be cured completely, and currently the main purpose of relief is through the use of anti-inflammatory and antirheumatic drugs, hormones, and biological agents. Tofacitib is a new type of small molecule inhibitor, which has a good effect in the treatment of RA. The current direct drug delivery method has serious side effects caused by the systemic distribution of the drug, so there is a need to develop an intelligent drug delivery system to realize precise treatment. In this work, tofacitib, gallic acid, targeted molecule folic acid, and Fe(III) were selected to assemble a novel type of artificial controllable nanodrug GF-TF. The self-photoacoustic/magnetic resonance imaging (self-PA/MRI) monitored the enrichment of GF-TF in the lesion in real-time, and artificially regulated the addition of deferoxamine (DFO) at the optimal enrichment. DFO strongly chelates Fe(III) in GF-TF and causes its structure to disintegrate gradually, and the self-PA/MRI signal of GF-TF became weaker while tofacitib began to be released, thus realizing the precise and artificially controlled release of the drug under the guidance of imaging. This nanodrug not only achieves efficient aggregation of drugs in inflamed joints, but also achieves real-time monitoring and precise control of drug release through self-PA/MRI, providing a new strategy for the precise treatment of RA.

Osteoarthritic Bony Alterations of Temporomandibular Joint and Relation to Low Bone Mineral Density in Postmenopausal Edentulous Females.

This study aimed to evaluate the relationship between osteoarthritic bony alterations in the temporomandibular joint (TMJ) and general bone mineral density (BMD) in postmenopausal edentulous females. Cone beam computed tomography (CBCT) scans for both TMJs were acquired for 80 clinically asymptomatic patients (mean age 72 ± 8.8 y). Both lumbar spine and femoral neck measurements of BMD were performed using dual-energy X-ray absorptiometry (DXA). The most frequently observed bony alterations were flattening of the articular surface (47.5%), sclerosis (41.5%), subcortical cysts (10%), and erosions (5%). Osteophytes were not observed. No statistical differences were observed between those who had or did not have radiological signs of bony alterations according to age or DXA scores. The prevalence of radiological findings of degenerative TMJ bony alterations in clinically asymptomatic postmenopausal females did not confirm a connection with a generally low BMD.

Inhibition of the MALT1-LPCAT3 axis protects cartilage degeneration and osteoarthritis

The proinflammatory cytokines and arachidonic acid (AA)-derived eicosanoids play a key role in cartilage degeneration in osteoarthritis (OA). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) preferentially incorporates AA into the membranes. Our recent studies showed that MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) plays a crucial role in propagating inflammatory signaling triggered by IL-1β and other inflammatory mediators in endothelial cells. The present study shows that LPCAT3 expression was up-regulated in both human and mice articular cartilage of OA, and correlated with severity of OA. The IL-1β-induces cell death via upregulation of LPCAT3, MMP3, ADAMTS5, and eicosanoids via MALT1. Gene silencing or pharmacological inhibition of LPCAT3 or MALT1 in chondrocytes and human cartilage explants notably suppressed the IL-1β-induced cartilage catabolism through inhibition of expression of MMP3, ADAMTS5, and also secretion of cytokines and eicosanoids. Mechanistically, overexpression of MALT1 in chondrocytes significantly upregulated the expression of LPCAT3 along with MMP3 and ADAMTS5 via c-Myc. Inhibition of c-Myc suppressed the IL-1β-MALT1-dependent upregulation of LPCAT3, MMP3 and ADAMTS5. Consistent with the in vitro data, pharmacological inhibition of MALT1 or gene silencing of LPCAT3 using siRNA-lipid nanoparticles suppressed the synovial articular cartilage erosion, pro-inflammatory cytokines, and eicosanoids such as PGE2, LTB4, and attenuated osteoarthritis induced by the destabilization of the medial meniscus in mice. Overall, our data reveal a previously unrecognized role of the MALT1-LPCAT3 axis in osteoarthritis. Targeting the MALT1-LPCAT3 pathway with MALT1 inhibitors or siRNA-liposomes of LPCAT3 may become an effective strategy to treat OA by suppressing eicosanoids, matrix-degrading enzymes, and proinflammatory cytokines.Graphical

The BMP7-Derived Peptide p[63-82] Reduces Cartilage Degeneration in the Rat ACLT-pMMx Model for Posttraumatic Osteoarthritis.

Osteoarthritis (OA) is characterized by articular cartilage erosion, pathological subchondral bone changes, and signs of synovial inflammation and pain. We previously identified p[63-82], a bone morphogenetic protein 7 (BMP7)-derived bioactive peptide that attenuates structural cartilage degeneration in the rat medial meniscal tear-model for posttraumatic OA. This study aimed to evaluate the cartilage erosion-attenuating activity of p[63-82] in a different preclinical model for OA (anterior cruciate ligament transection-partial medial meniscectomy [anterior cruciate ligament transection (ACLT)-pMMx]). The disease-modifying action of the p[63-82] was followed-up in this model for 5 and 10 weeks. Skeletally mature male Lewis rats underwent ACLT-pMMx surgery. Rats received weekly intra-articular injections with either saline or 500 ng p[63-82]. Five and 10 weeks postsurgery, rats were sacrificed, and subchondral bone characteristics were determined using microcomputed tomography (µCT). Histopathological evaluation of cartilage degradation and Osteoarthritis Research Society International (OARSI)-scoring was performed following Safranin-O/Fast Green staining. Pain-related behavior was measured by incapacitance testing and footprint analysis. Histopathological evaluation at 5 and 10 weeks postsurgery showed reduced cartilage degeneration and a significantly reduced OARSI score, whereas no significant changes in subchondral bone characteristics were found in the p[63-82]-treated rats compared to the saline-treated rats. ACLT-pMMx-induced imbalance of static weightbearing capacity in the p[63-82] group was significantly improved compared to the saline-treated rats at weeks 5 postsurgery. Footprint analysis scores in the p[63-82]-treated rats demonstrated improvement at week 10 postsurgery. Weekly intra-articular injections of p[63-82] in the rat ACLT-pMMx posttraumatic OA model resulted in reduced degenerative cartilage changes and induced functional improvement in static weightbearing capacity during follow-up.

Tranexamic Acid Attenuates the Progression of Posttraumatic Osteoarthritis in Mice

Background: Posttraumatic osteoarthritis (OA) is a common disorder associated with a high socioeconomic burden, particularly in young, physically active, and working patients. Tranexamic acid (TXA) is commonly used in orthopaedic trauma surgery as an antifibrinolytic agent to control excessive bleeding. Previous studies have reported that TXA modulates inflammation and bone cell function, both of which are dysregulated during posttraumatic OA disease progression. Purpose: To evaluate the therapeutic effects of systemic and topical TXA treatment on the progression of posttraumatic OA in the knee of mice. Study Design: Controlled laboratory study. Methods: OA was induced via anterior cruciate ligament (ACL) transection on the right knee of female mice. Mice were treated with TXA or vehicle intraperitoneally daily or intra-articularly weekly for 4 weeks, starting on the day of surgery. Articular cartilage degeneration, synovitis, bone erosion, and osteophyte formation were scored histologically. Micro−computed tomography evaluation was conducted to measure the subchondral bone microstructure and osteophyte volume. Cartilage thickness and bone remodeling were assessed histomorphometrically. Results: Both systemic and topical TXA treatment significantly reduced cartilage degeneration, synovitis, and bone erosion scores and increased the ratio of hyaline to calcified cartilage thickness in posttraumatic OA. Systemic TXA reversed ACL transection-induced subchondral bone loss and osteophyte formation, whereas topical treatment had no effect. Systemic TXA decreased the number and surface area of osteoclasts, whereas those of osteoblasts were not affected. No effect of topical TXA on osteoblast or osteoclast parameters was observed. Conclusion: Both systemic and topical TXA exerted protective effects on the progression of posttraumatic OA. Drug repurposing of TXA may, therefore, be useful for the prevention or treatment of posttraumatic OA, particularly after ACL surgery. Clinical Relevance: TXA might be beneficial in patients with posttraumatic OA of the knee.

A bioactive and biodegradable vitamin C stearate-based injectable hydrogel alleviates experimental inflammatory arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disorder affecting nearly 1% of the global population. In RA, synovial joints are infiltrated by inflammatory mediators and enzymes, leading to articular cartilage deterioration, joint damage, and bone erosion. Herein, the 9-aminoacridine-6-O-stearoyl-L-ascorbic acid hydrogel (9AA-SAA hydrogel) was formulated by the heat-cool method and further characterized for surface charge, surface morphology, rheology, and cytocompatibility. Furthermore, we evaluated the therapeutic efficacy of the 9AA-SAA hydrogel, an enzyme-responsive drug delivery system with on-and-off switching capabilities based on disease severity against collagen-induced experimental arthritis in Wistar rats. The anti-inflammatory action of the US FDA-approved drug 9-aminoacridine (9AA) was revealed which acted through nuclear receptor subfamily 4 group A member 1 (NR4A1), an anti-inflammatory orphan nuclear receptor that inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Furthermore, we have explored the role of ascorbic acid, an active moiety of 6-O-stearoyl-L-ascorbic acid (SAA), in promoting the production of collagen production through ten-eleven translocation-2 (TET2) upregulation. Targeting through NR4A1 and TET2 could be the probable mechanism for the treatment of experimental arthritis. The combination of 9AA and ascorbic acid demonstrated enhanced therapeutic efficacy in the 9AA-SAA hydrogel, significantly reducing the severity of experimental arthritis. This approach, in contrast to existing treatments with limited effectiveness, presents a promising and more effective strategy for RA treatment by mitigating inflammation in experimental arthritis.

Carveol alleviates osteoarthritis progression by acting on synovial macrophage polarization transformation: An in vitro and in vivo study

Osteoarthritis (OA) is a heterogeneous disease that affects the entire joint. Its pathogenesis involves hypertrophy and hyperplasia of synovial cells and polarization infiltration of macrophages, in which macrophages, as a potential target, can delay the progression of the disease by improving the immune microenvironment in OA. To investigate the role and regulatory mechanism of Carveol in cartilage and synovial macrophage reprogramming and crosstalk during the development of OA. RAW264.7 mouse macrophage cell line was mainly used to stimulate macrophages to polarization towards M1 and M2 by LPS, IL4+IL13, respectively. Different concentrations of Carveol were given to intervene, and macrophage culture medium was collected to intervene mouse C57BL6J chondrocytes. ROS assay kit, western blotting, cellular immunofluorescence, scanning microscope and section histology were used to evaluate the effect of Carveol on anti-M1-polarization, M2-polarization promotion and cartilage protection. The mouse destabilization of medial meniscus (DMM) model was observed by micro-CT scan and histology. We found that CA could inhibit the increase of macrophage inflammation level under the intervention of LPS and promote the production of M2 anti-inflammatory substances under the intervention of IL-4+IL13. In addition, Carveol activated NRF2/HO-1/NQO1 pathway and enhanced ROS clearance in chondrocytes under the intervention of macrophage culture medium. The phosphorylation of I-κBα is inhibited, which further reduces the phosphorylation of P65 downstream of nuclear factor-κB (NF-κB) signaling pathway. In addition, Carveol inhibits mitogen activated protein kinase (MAPK) signaling molecules P-JNK, P-ERK and P–P38, and inhibits the production of inflammatory mediators. In vivo, Carveol can reduce osteophytes and bone spurs induced by DMM, reduce hypertrophy of synovial cells, reduce infiltration of macrophages, inhibit subchondral bone destruction, and reduce articular cartilage erosion. Our study suggests that synovial macrophages are potential targets for OA treatment, and Carveol is an effective candidate for OA treatment.

Assessment of bony changes in temporomandibular joint in patients using cone beam computed tomography – a cross sectional study

Background and aimThe aim of this study is to evaluate the changes in the temporomandibular joint (TMJ) in patients with temporomandibular disorder (TMD) and the relationship between age, sex, and types of TMJ change using Cone Beam Computed Tomography (CBCT).Methods and materialCBCT records of 200 patients (123 women and 67 men) were retrieved and assessed. Right and left TMJs were evaluated separately, resulting in a total of 400 TMJs. The images were analyzed using On demand 3D Application The radiographic findings were classified as erosion, proliferative changes mainly, including flattening and osteophytes of the condyle, sclerosis, Ely cyst, hypoplasia and hyperplasia of the condyles, ankylosis, and joint cavity. Data analysis was performed using descriptive statistics, paired T-tests, and repeated measure ANOVA (Analysis of Variance) in SPSS Software.ResultsThe most prevalent types of condylar bony changes observed was osteophyte (63.5%) followed by flattening of the articular surface (42%), erosion (40%), ankylosis (10%) and sclerosis (10%). 7.5% of joints showed hyperplastic condyles but only 2% showed hypoplasia. The least prevalent change observed was Ely Cyst (1%). Osteophyte was the most prevalent change observed in all age groups and both sexes except for men aged 31 ~ 50, where flattening was more frequent. A statistically significant difference was found between sex and prevalence of erosion in the age group of 10 ~ 30 (P = 0.001); as well as between sex and condylar hyperplasia in the same age group.ConclusionBased on the findings of this research, the prevalence of bony changes of TMJ from highest to lowest is as follows: osteophyte, flattening of the articular surface, erosion, ankylosis, sclerosis, hyperplastic condyles, hypoplastic condyles and Ely Cyst. CBCT is an accurate 3 dimensional imaging modality for assessment of TMJ bony structures.

An in vitro and in vivo study: Valencene protects cartilage and alleviates the progression of osteoarthritis by anti-oxidative stress and anti-inflammatory effects

BackgroundOsteoarthritis (OA) is a heterogeneous disease involving the whole joint. The pathogenesis involves oxidative stress levels and chronic inflammation, and Valencene (VA) has excellent anti-inflammatory and antioxidant stress abilities. PurposeThe objective was to study the effects of VA therapy on combating oxidative stress and to evaluate the protective effect of chondrocytes to alleviate the progression of OA. MethodsC57BL6J mouse chondrocytes were used as the primary cells in this study. Mouse chondrocytes were stimulated with IL-1β, and VA was administered in different concentrations. Reactive oxygen species (ROS) assay kits, western blotting, cellular immunofluorescence, and scanning microscopy were used to evaluate VA's antioxidant stress mechanism, anti-inflammatory effect, and cartilage protective ability. The mouse arthritis model constructed by destabilization of medial meniscus (DMM) was observed by micro-CT scan and histology after different treatments. ResultsWe found that VA can reverse the rise of ROS under IL-1β, the degeneration of the cartilage extracellular matrix, and the production of inflammatory mediators. In terms of mechanism, VA activated NRF2/HO-1/NQO1 pathway, thus enhancing ROS clearance. The phosphorylation of IκBα is inhibited, which further reduces the downstream phosphorylation of P65 in nuclear factor-κB (NF-κB) signaling. In addition, VA inhibited mitogen-activated protein kinase (MAPK) signaling molecules P-JNK, P-ERK, and P-P38, inhibiting the production of inflammatory mediators and thus inhibiting Aggrecan and Collagen Type II （COL2）degeneration. In vivo, VA reduced DMM-induced osteophytes and spurs, suppressed subchondral bone destruction, and reduced articular cartilage erosion. ConclusionOur study demonstrated that VA is an effective candidate for OA treatment.

Schnurri-3 inhibition suppresses bone and joint damage in models of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to systemic and articular bone loss by activating bone resorption and suppressing bone formation. Despite current therapeutic agents, inflammation-induced bone loss in RA continues to be a significant clinical problem due to joint deformity and lack of articular and systemic bone repair. Here, we identify the suppressor of bone formation, Schnurri-3 (SHN3), as a potential target to prevent bone loss in RA. SHN3 expression in osteoblast-lineage cells is induced by proinflammatory cytokines. Germline deletion or conditional deletion of Shn3 in osteoblasts limits articular bone erosion and systemic bone loss in mouse models of RA. Similarly, silencing of SHN3 expression in these RA models using systemic delivery of a bone-targeting recombinant adenoassociated virus protects against inflammation-induced bone loss. In osteoblasts, TNF activates SHN3 via ERK MAPK-mediated phosphorylation and, in turn, phosphorylated SHN3 inhibits WNT/β-catenin signaling and up-regulates RANKL expression. Accordingly, knock-in of a mutation in Shn3 that fails to bind ERK MAPK promotes bone formation in mice overexpressing human TNF due to augmented WNT/β-catenin signaling. Remarkably, Shn3-deficient osteoblasts are not only resistant to TNF-induced suppression of osteogenesis, but also down-regulate osteoclast development. Collectively, these findings demonstrate SHN3 inhibition as a promising approach to limit bone loss and promote bone repair in RA.

A Non-targeted Metabolomics Reveals Therapeutical Effect and Mechanism of Sanmiao Pill on Adjuvant-induced Arthritis Rats.

Rheumatoid arthritis (RA) is an increasingly serious disease worldwide that can damage the joints and bones of sufferers. Sanmiao Pill (SMP), a classical traditional Chinese medicine (TCM) prescription, has been used for effective treatments for RA in the clinic. To comprehensively illuminate the therapeutic mechanism of SMP in the treatment of RA, the effects of SMP on biomarkers and metabolic pathways in rats with adjuvant-induced arthritis (AIA) were examined. > Methods: Sprague Dawley rats were randomly divided into two control (CC, Control) groups, two model (MM, Model) groups, a methotrexate group (MTX, 7.6 mg/kg body weight per week), and two SMP groups (San-L, 28.7 mg/kg body weight per day and San-H, 57.4 mg/kg body weight per day). Rats' body weight, paw swelling, arthritis scores, biochemical parameters, histopathology, and so on were used to evaluate the success of the model and the therapeutic effects of SMP. The metabolic techniques were used to characterize the metabolic profile and biomarkers of the serum and urine samples of rats to reveal the metabolic changes that occurred after SMP treatment. > Results: After 21 days of treatment, SMP improved weight gain, reduced the severity of paw swelling, lowered the levels of biochemical indicators (CCP-Ab, IL-6, TNF-α, RF), decreased destruction of articular cartilage and bone erosion, and protected the affected joints.Additionally, 17 and 19 potential biomarkers associated with RA were identified in the serum and urine, respectively. SMP significantly reversed 14 potential biomarkers, such as arachidonic acid, lysoPC(20:4(5Z,8Z,11Z,14Z)), L-tryptophan, 9-cis-Retinoic acid, hippuric acid, pyridoxine, and pantothenic acid. These metabolites are associated with arachidonic acid metabolism, glycerophospholipid catabolism, tryptophan metabolism, phenylalanine metabolism, vitamin B6 metabolism, etc. > Conclusion: These results indicated that RA-related biomarkers reflected the metabolic profile of AIA rats. Meanwhile, SMP could effectively treat RA mainly by reducing inflammation and regulating abnormal lipid metabolic pathways and amino acid metabolisms. It showed that metabolomics could be used to analyze the metabolic profiles involved in RA and reveal the mechanism of SMP treatment of RA.>.

Inhibition of histone lysine demethylase 6A promotes chondrocytic activity and attenuates osteoarthritis development through repressing H3K27me3 enhancement of Wnt10a.

Histone hypermethylation represses gene transcription, which affects cartilage homeostasis or joint remodeling. Trimethylation of lysine 27 of histone 3 (H3K27me3) changes epigenome signatures, regulating tissue metabolism. This study aimed to investigate whether loss of H3K27me3 demethylase Kdm6a function affected osteoarthritis development. We revealed that chondrocyte-specific Kdm6a knockout mice developed relatively long femurs and tibiae as compared to wild-type mice. Kdm6a deletion mitigated osteoarthritis symptoms, including articular cartilage loss, osteophyte formation, subchondral trabecular bone loss, and irregular walking patterns of destabilized medial meniscus-injured knees. In vitro, loss of Kdm6a function compromised the loss in expression of key chondrocyte markers Sox9, collagen II, and aggrecan and improved glycosaminoglycan production in inflamed chondrocytes. RNA sequencing showed that Kdm6a loss changed transcriptomic profiles, which contributed to histone signaling, NADPH oxidase, Wnt signaling, extracellular matrix, and cartilage development in articular cartilage. Chromatin immunoprecipitation sequencing uncovered that Kdm6a knockout affected H3K27me3 binding epigenome, repressing Wnt10a and Fzd10 transcription. Wnt10a was, among others, functional molecules regulated by Kdm6a. Forced Wnt10a expression attenuated Kdm6a deletion-induced glycosaminoglycan overproduction. Intra-articular administration with Kdm6a inhibitor GSK-J4 attenuated articular cartilage erosion, synovitis, and osteophyte formation, improving gait profiles of injured joints. In conclusion, Kdm6a loss promoted transcriptomic landscapes contributing to extracellular matrix synthesis and compromised epigenetic H3K27me3-mediated promotion of Wnt10a signaling, preserving chondrocytic activity to attenuate osteoarthritic degeneration. We highlighted the chondroprotective effects of Kdm6a inhibitor for mitigating the development of osteoarthritic disorders.

Los Polimorfismos en la Uteroglobina y en IL2R están asociados con el daño articular y/o la Cirugía articular en pacientes con Artritis Reumatoide

Introduction and Objectives. Of all clinical manifestations that mark prognosis of a patient with RA, radiological damaged is considered one of the most important variables. In addition to clinical and laboratory markers are increasingly studying the influence of genetic factors in the predictive ability of the RA forecast. Previous studies have reported misleading results about polymorphisms in different genes associated with radiological damage in RA. The aim of this study was to assess the involvement of the clinical, analytical and genetic variables in the radiological damage in a Spanish RA population. Methods. Six hundred thirty-two Spanish RA patients were included. SNP genotyping was performed using an oligonucleotide microarray. Allele and genotype association analyses with articular damage and a haplotype association test were performed. Results. This study includes retrospectively 604 Spanish RA patients with articular erosions and 616 with surgery due to RA. The A587G polymorphism (rs3741240) in uteroglobin gene was associated with increased radiological damage defined by phenotypes RX2 (multiple erosions on hands and feet) and surgery due to RA (OR 1.6 and 1.7 respectively). IL2R polymorphism was associated with RX2 phenotype (OR 2.95). Disease duration, painful joints, ESR, RF and ACPA are the analytical and clinical variables significantly associated with articular damage. Conclusions. These results demonstrate that the A587G and C4599T polymorphism in uteroglobin and IL2R genes respectively are associated with radiological damage in a Spanish RA population.

FIBRONECTIN TYPE III DOMAIN CONTAINING 5 MITIGATES CHONDROCYTE SENESCENCE, SUBCHONDRAL OSTEOCLAST FORMATION, AND OSTEOARTHRITIS DEVELOPMENT THROUGH INHIBITING INTERLEUKIN-6

Senescent chondrocyte and subchondral osteoclast overburden aggravate inflammatory cytokine and pro-catabolic proteinase overproduction, accelerating extracellular matrix degradation and pain during osteoarthritis (OA). Fibronectin type III domain containing 5 (FNDC5) is found to promote tissue homeostasis and alleviate inflammation. This study aimed to characterize what role Fndc5 may play in chondrocyte aging and OA development.Serum and macroscopically healthy and osteoarthritic cartilage were biopsied from patients with knee OA who received total knee replacement. Murine chondrocytes were transfected with Fndc5 RNAi or cDNA. Mice overexpressing Fndc5 (Fndc5Tg) were operated to have destabilized medial meniscus mediated (DMM) joint injury as an experimental OA model. Cellular senescence was characterized using RT-PCR analysis of p16INK4A, p21CIP1, and p53 expression together with ß-galactosidase activity staining. Articular cartilage damage and synovitis were graded using OARSI scores. Osteophyte formation and mechanical allodynia were quantified using microCT imaging and von Frey filament, respectively. Osteoclast formation was examined using tartrate-resistant acid phosphatase staining.Senescent chondrocyte and subchondral osteoclast overburden together with decreased serum FNDC5 levels were present in human osteoarthritic cartilage. Fndc5 knockdown upregulated senescence program together with increased IL-6, MMP9 and Adamts5 expression, whereas Alcian blue-stained glycosaminoglycan production were inhibited. Forced Fndc5 expression repressed senescence, apoptosis and IL-6 expression, reversing proliferation and extracellular matrix production in inflamed chondrocytes. Fndc5Tg mice showed few OA signs, including articular cartilage erosion, synovitis, osteophyte formation, subchondral plate sclerosis and mechanical allodynia together with decreased IL-6 production and few senescent chondrocytes and subchondral osteoclast formation during DMM-induced joint injury. Mechanistically, Fndc5 reversed histone H3K27me3-mediated IL-6 transcription repression to reduce reactive oxygen species production.Fndc5 loss correlated with OA development. It was indispensable in chondrocyte growth and anabolism. This study sheds light onto the anti-ageing and anti-inflammatory actions of Fndc5 to chondrocytes; and highlights the chondroprotective function of Fndc5 to compromise OA.

Cartilage-targeting and inflammatory-responsive nanocarriers for effective osteoarthritis treatment via reactive oxygen species scavenging and anti-angiogenesis

Osteoarthritis (OA), a common disabling joint disease, is highly associated with microenvironmental changes in the cartilage and subchondral bone. Elevated reactive oxygen species (ROS) in the cartilage and subchondral bone angiogenesis accelerate articular cartilage erosion. New cartilage-targeting drug delivery systems that are aimed at preventing ROS production and angiogenesis may be of clinical significance for OA treatment. Herein, an ROS scavenger and an inflammatory-responsive nanocarrier are designed by immobilizing the natural polyphenol (curcumin) in chitosan-catechol nanoformulations (Cur-CS-C NPs) via boronate ester. The robust cartilage-targeting effects and ROS scavenging capacities of Cur-CS-C NPs were respectively determined in cartilage explants and chondrocytes. Intra-articular injection of Cur-CS-C NPs in OA rat models efficiently suppressed angiogenesis and cartilage degradation partially via the ROS-mediated NF-κB/PI3K-Akt signaling pathway. The developed curcumin-functionalized nanocarriers can significantly delay OA progression and provide a promising therapeutic strategy for other inflammatory diseases that are characterized by oxidative stress and angiogenesis.

Incidental findings involving the temporomandibular joint on computed tomography and magnetic resonance imaging.

The temporomandibular joint (TMJ) is frequently imaged in head and neck computed tomography (CT) and magnetic resonance imaging (MRI) studies. Depending on the indication for the study, an abnormality of the TMJ may be an incidental finding. These findings encompass both intra- and extra-articular disorders. They may also be related to local, regional or systemic conditions. Familiarity with these findings along with pertinent clinical information helps narrow the list of differential diagnoses. While definitive diagnosis may not be immediately apparent, a systematic approach contributes to improved discussions between clinicians and radiologists and better patient management.

PIGMENTED VILLONODULAR SYNOVITIS OF HIP: A RARE CASE

Pigmented villonodular synovitis (PVNS) is a rare disease that can affect any joint, bursa or tendon sheath. The hip is less frequently affected than the knee.1 We report a case of a 46 years old male presented with history of pain and limp over right hip since 6months associated with difculty in sitting cross legged and squatting to performing day today activity. There was no history of fever, weight loss, and long term drug intake. Radiological assessment showed secondary arthritis of right hip with features of avascular necrosis (AVN). The provisional diagnosis was Arthritis of right hip secondary to AVN/ Inammatory arthritis and the patient underwent uncemented right total hip replacement(THA), Intra operatively the articular erosion was noted with reddish gray abnormal synovial growth. Histological assessment showed diffuse expansive sheets of histiocytes admixed with hemosiderin laden macrophages and alveolar spaces lined by synovial cells and collagenized stroma. A short term follow up of 18months did not show any clinical recurrence. We conclude that, from our observation, complete excision of lesion combined with THA is an effective treatment for PVNS of Hip.

Comparative evaluation of effect of various means of basic and genetically engineered biological therapy on clinical course, rate of development of osteodestructive changes, quality of life and state of stress resistance in patients with rheumatoid arthritis (open observational study)

Objective. To study the effect of various basic and genetic engineering biological therapies (infliximab, rituximab, tocilizumab) used as first, second- and third-line drugs in combination with methotrexate on clinical course, quality of life (QOL), and the evolution of articular erosions and synovitis in patients with rheumatoid arthritis (RA) during 12 months of follow-up.Material and methods. This paper is an open observational study of the efficacy and safety of various basic and genetic engineering biological therapy agents (bDMARD) in patients with early active RA who are in the Mechnikov North-West State Medical University registry. Included are 151 patients with early RA (eRA), the average age is 58.2 ± 5.5 years, the disease duration is 6.5 ± 0.3 months, DAS 28-CRP – 4.48 ± 0.87. At the first stage, basic therapy was administered to patients with eRA by random sampling: sulfasalazine (CC) 2 g per day (group I – 55 patients), methotrexate (MT) – 20 mg per week (group II – 55 patients), or leflunomide (LF) 20 mg per day (group III – 41 patients). The follow-up was 12 months. At the second stage, 101 patients with persisting moderate (DAS 28: 3.2–5.1) and high levels of RA activity (DAS 28 > 5.1) despite ongoing therapy with DMARDs were assigned MT at a dose of 25 mg per week (subgroup 1–25 patients), or MT – 20 mg per week in combination with infliximab (INF) – 3 mg/kg (subgroup of 2–25 patients), or – MT 20 mg per week and rituximab (RM) – two infusions of 1000 mg at the week 0 and 2 and then at the week 52nd and 54th with a duration of observation of 12 months. In the third stage, 20 patients (16 women and 4 men aged 28 to 67 years) with a high disease activity DAS 28-CRP despite previous therapy with MT and INF or RM were transferred to therapy with an IL6 – tocilizumab receptor blocker as a second-line or third-line drug. The duration of observation ranged from 6 months to five years.Results. By 12 months of treating DMARDs, clinical remission was achieved more often in the MT group than in the LF group (43.2 and 32.4 %) (p < 0.05), and was accompanied by a decrease in the expression of markers of early activation of T-lymphocytes, IL-1β, IL-2 and IL-4. In the SS group, clinical remission was not observed, while there was a significant increase in the median of the total Sharpe score and erosion score relative to the baseline. The prescription of INF or PM as the first bDMARD after 12 months led to a significant increase in the physical and psychological components of the patients' QL and positive dynamics of the HAQ index compared to baseline values. The use of tocilizumab as a second-line and third-line drug in patients with active RA and the ineffectiveness of previous therapy for DMARD and bDMARD contributed to a significant decrease in DAS 28-CRP by as early as 24 weeks of follow-up. Cases of serious adverse reactions (AE) are not marked.Conclusions. There were no statistically significant differences in the dynamics of CRP, ESR, circulating immune complex and X-ray progression indicators between the groups of patients who received biological therapy of INF and RM, which confirms the possibility of ‘switching’ therapy from the first bDMARD to the drugs of subsequent lines with an increase in the clinical activity of RA. Tocilizumab can be a second- and third-line drug with an ‘escape’ effect from other bDMARDs.

Paper 42: Effects of Blood Type Mismatching on Functional Graft Survival after Osteochondral Allograft Transplantation

Objectives:To explore a factor that may contribute to potentially detrimental sub-rejection immune responses, we compared donor and recipient blood types following osteochondral allograft (OCA) transplants from a subset of patients in an IRB-approved dedicated lifelong registry to determine potential relationships for blood type mismatches with documented graft failures. The study was designed to test the hypothesis that OCA transplantation patients receiving blood type mismatched allografts would be more likely to require OCA revision or artificial arthroplasty surgery compared to those receiving donor-recipient matched allografts.Methods:A subset of patients was selected from those enrolled (n=414) in our center’s IRB-approved lifelong registry for OCA transplantation clinical outcomes. This subset included patients with complete donor and recipient ABO and Rh Factor data available such that there was a 2:1 ratio of successful versus failed outcomes for age-, BMI-, and joint-matched OCA transplant recipients for statistical analyses. Donor blood type information was obtained from the respective tissue banks. Recipient blood type information was obtained from electronic medical records. Patients who required OCA revision or artificial arthroplasty were defined as graft failures. Outcomes were assessed for all patients included in the blood type mismatching analyses. Osteochondral tissues that were resected from the knee, hip, and ankle of patients undergoing standard-of-care revision or arthroplasty surgeries, and that otherwise would be discarded, were recovered for histologic assessments. Subjective histologic assessments were performed by a pathologist who was blinded to patient demographics, blood typing information, outcomes data, and tissue source. When aggregates of lymphocytes and plasma cells were observed surrounding small blood vessels (consistent with an immune response), immunohistochemistry for CD3, CD8, and CD20 was performed to further characterize the lymphocytes (T cell marker, cytotoxic T lymphocytes, and B cell marker, respectively) for subjective assessment of relevant immune responses. Subjects were grouped by ABO blood type, Rh Factor, and both. Histologically evaluated failures were separated by immune response as positive or negative. Fisher’s exact tests were used for statistical analyses with a p-value of less than 0.05 set a priori to define statistical significance.Results:A total of 103 patients were included for analysis with 33 of these requiring OCA revision or artificial arthroplasty. Of the clinical failures, 18 had previously transplanted osteochondral allograft tissues recovered for histological assessment. Twelve (66%) of these recovered OCAs had aggregates of CD3+, CD8+, and CD20+ lymphocytes around small blood vessels in the bone marrow spaces and adipose/collagenous tissue of the previously transplanted allograft. The remaining resected OCAs (34%) did not show a similar pattern of T- and B-cell infiltrates around blood vessels. Other histologic abnormalities associated with failed OCAs included avascular necrosis, subchondral micro and macro fractures, subchondral collapse, and/or articular cartilage erosion or delamination. No statistically significant differences in proportions for success versus failure based on mismatches for ABO type, Rh Factor, or both were noted. Similarly, no statistically significant differences in proportions for positive versus negative immune responses based on mismatches for ABO type, Rh Factor, or both were noted.Conclusions:Donor-recipient mismatches for ABO blood type and/or Rh Factor were not associated with higher likelihood for patients to require OCA revision or artificial arthroplasty surgery. Similarly, donor-recipient mismatches for ABO blood type and/or Rh Factor were not associated with higher likelihood for positive immune responses in previously implanted OCA tissues recovered from patients who required revision or artificial arthroplasty surgeries. However, two-thirds of the tissues recovered from graft failure cases had T- and B-cell infiltrates, suggesting sub-rejection immune responses occur after OCA transplantation that should be further investigated to determine potential mechanistic relationships with graft failures. The results of the present study support current clinical practice for transplantation of fresh OCAs, which does not require HLA or blood type matching or immunosuppressive medication for recipients. However, histologic assessments suggest that sub-rejection immune responses may play a role in graft failures and should be further investigated.