Targeting Proteinase Activated Receptor-4 Reduces Mechanonociception During the Acute Inflammatory Phase but not the Chronic Neuropathic Phase of Osteoarthritis in Rats

Serine proteases are elevated in arthritic joints where they can cleave protease activated receptors (PARs) to modulate pain and inflammation. Activation of protease-activated receptor 4 (PAR4) has been implicated in inflammatory joint pain. Whether PAR4 is involved in osteoarthritis (OA) pain has not yet been explored. The aim of this study was to compare the role of PAR4 in modulating early versus late stage OA pain using two models of OA viz. monoiodoacetate (MIA) and medial meniscal transection (MMT). G-ratio calculation and electron microscopy analysis revealed saphenous nerve demyelination and structural damage during late stage but not early OA in both models. Using immunohistochemistry, neuronal expression of PAR4 was higher in early versus late OA. Systemic administration of the PAR4 antagonist pepducin P4pal10 reduced both secondary allodynia (von Frey hair algesiometry) and joint nociceptor firing (single unit recordings) in MMT and MIA animals compared to vehicle-treated animals in early OA. The PAR4 antagonist was ineffective at altering pain or joint afferent firing in post-inflammatory OA. During the acute phase of the models, joint inflammation as determined by laser speckle contrast analysis and intravital microscopy could be partially blocked by pepducin P4pal10. Compared to late-stage disease, inflammatory cytokines were elevated in early MIA and MMT rats. These findings suggest that PAR4 may be a viable target to treat the pain of early onset OA or during episodic inflammatory flares.

Efficacy of intra-articular injection of combined platelet-rich plasma and hyaluronic acid in knee degenerative joint disease (182)

Objectives: Osteoarthritis (OA) of the knee is a debilitating disease whose prevalence has increased across the world with aging population. Platelet-Rich Plasma (PRP) and Hyaluronic Acid (HA) injections appear to be two of the main strategies for conservative treatment of early knee OA. The effectiveness of both treatments, however, is still under debate because contrasting results have been described in the current literature. Some pre-clinical studies evaluated the association of PRP and HA with encouraging results, highlighting the possibility of a synergistic effect between the two compounds and suggesting a possible use through combined intra-articular injections. The aim of this prospective randomized controlled double-blind clinical trial is to evaluate the efficacy of intra-articular injections of PRP and HA for the treatment of early stages of knee degenerative joint disease in improving joint function and reducing pain, compared to the intra-articular injections of PRP and HA alone. Methods: Patients with knee early OA were prospectively enrolled and then double-blinded randomly divided into three groups of fifty-eight subjects each: HA alone, PRP alone and PRP+HA group. Patients received three intra-articular injections with two-week interval period among each dose. Patients clinical outcome was evaluated through five questionnaires [The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Tegner Activity, Visual Analogue Scale (VAS), Knee injury and Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee (IKDC) Subjective Knee Form] before the treatment (T0) and after 3, 6 and 12 months from the first injection. Patients’use of paracetamol and supplementary analgesia for knee pain during the study was collected. Results: One hundred and seventy-four patients were enrolled in this study (age, 30-80 years; 108 females and 66 males) and 162 completed the 12-month follow-up. All patients showed significant clinical improvement after treatment. The analysis of covariance (ANCOVA) did not show statistically significant differences among the three groups for all the variables analysed at 6 and 12 months of follow-up (p>0.05).No significant differences were found in terms of adverse events (p=0.49) among the three groups of patients (p=0.92).The demand for paracetamol and supplementary analgesics was generally low and there were no significant differences among the groups (p=0.23 and p=0.56, respectively). Conclusions: Injections treatments for early knee OA are an important conservative therapeutic strategy. To date, the current literature presents many contrasting studies about the effectiveness of PRP or HA, but only a few consider the combined use of PRP and HA as attractive therapeutic option. Our study has not shown any significant difference in clinical and functional outcomes among the three experimental groups, suggesting a substantial equivalence of these three treatments. Thus, cost-effectiveness is in favor of HA injections in the conservative treatment of early OA.

Changes in Hematobiochemical, Radiological, and Synovial Fluid Parameter in Patients of Osteoarthritis Knee with Effusion: A Prospective Observational Study

Introduction: A joint is the point of connection between two bones in our body. Inflammation of joint leads to several diseases, including osteoarthritis (OA). OA is a common condition of debilitating joint disease mainly affecting the elderly. Case Report:e In this study, we had studied correlation the cases (OA with synovial effusion) and control (OA without synovial effusion) with blood parameters, radiological and synovial fluid parameters (tumor necrosis factor-? [TNF]-? levels), and the incidence of synovial effusion in radiological staging of disease. Out of 100 patients, 50 patients with OA knee with effusion and 50 patients OA knee without effusion. We concluded that incidence of synovitis knee along with raised markers of inflammation, that is, C-reactive protein, erythrocyte sedimentation rate, and synovial fluid TNF-? levels was significantly higher in Stage II of OA knee, indicating that inflammation is significant part of early OA knee. Inflammation in early part of disease can lead to articular cartilage damage and rapid progression of osteoarthritic changes. Conclusion:Our study concluded that OA is not only a degenerative disease but also there is significant contribution of inflammation in disease process. Targeting inflammation in synovium may delay/prevent articular cartilage damage and osteophytes formation, especially in early OA. Anti-TNF-? agents and anti-inflammatory drugs may be considered for definitive treatment of OA. Keywords: Tumor necrosis factor-alpha, osteoarthritis, Kellgren Lawrence.

Platelet-Rich plasma injections treatment in patients having early osteoarthritis of knee joint.

Objective: To find out the outcome following intra-articular platelet-rich plasma (PRP) injection in patients having early OA of knee. Study Design: Prospective Study. Setting: Tahira Jamshed Medical Complex, Bahawalpur. Period: January 2019 to February 2020. Material & Methods: A total of 112 cases of both gender, aged 40 to 60 years, Grade I and Grade II OA, having symptoms of OA for a minimum duration of 1 year, were enrolled. All participants were assessed for physical activity and pain linked with arthritis as per “Western Ontario and McMaster University Arthritis Index (WOMAC) score”. Results: Out of a total 98 cases who completed the study, majority 58 (59.2%) were female, 67 (68.4%) had Kellgren-Lawrence Grade-I OA and 81 (82.7%) were experiencing OA symptoms with a duration of less than 2 years. The difference between mean WOMAC score before the treatment (80.38+6.3) and after PRP treatment (42.93+6.9) turned out to be statistically significant (p value < 0.001). After the treatment, cases having duration of symptoms of OA as less than 2 years had significantly less WOMAC score (p value = 0.0418). Conclusion: PRP treatment in patients having early OA seemed to be quite efficacious. The effects of PRP injections were more favorable in cases having clinical symptoms of OA for less than 2 years of duration.

An In Vitro System to Study the Effect of Subchondral Bone Health on Articular Cartilage Repair in Humans

Chondrocyte-based cartilage repair strategies, such as articular chondrocyte implantation, are widely used, but few studies addressed the communication between native subchondral bone cells and the transplanted chondrocytes. An indirect co-culture model was developed, representing a chondrocyte/scaffold-construct repair of a cartilage defect adjoining bone, where the bone could have varying degrees of degeneration. Human BM-MSCs were isolated from two areas of subchondral bone in each of five osteochondral tissue specimens from five patients undergoing knee arthroplasty. These two areas underlaid the macroscopically and histologically best and worst cartilage, representing early and late-stage OA, respectively. BM-MSCs were co-cultured with normal chondrocytes suspended in agarose, with the two cell types separated by a porous membrane. After 0, 7, 14 and 21 days, chondrocyte–agarose scaffolds were assessed by gene expression and biochemical analyses, and the abundance of selected proteins in conditioned media was assessed by ELISA. Co-culture with late-OA BM-MSCs resulted in a reduction in GAG deposition and a decreased expression of genes encoding matrix-specific proteins (COL2A1 and ACAN), compared to culturing with early OA BM-MSCs. The concentration of TGF-β1 was significantly higher in the early OA conditioned media. The results of this study have clinical implications for cartilage repair, suggesting that the health of the subchondral bone may influence the outcomes of chondrocyte-based repair strategies.