Search Results (77)

Osteoarthritis (OA) is a multifactorial degenerative joint disease in which aberrant mechanical cues act in concert with metabolic dysregulation and chronic low-grade inflammation, with chondrocyte hypertrophy representing a key pathological event driving cartilage degeneration. Alterations in extracellular matrix (ECM) properties—including mechanical loading, stiffness and viscoelasticity, topological organization, and surface chemistry—regulate hypertrophic differentiation and matrix degradation in a zone-, stage-, and scale-dependent manner. Microscale measurements often reveal localized stiffening in superficial zones during early OA, whereas bulk tissue testing can show softening or heterogeneous changes in deeper zones or advanced stages, highlighting the context-dependent nature of ECM mechanics. These biophysical signals are sensed by integrin-based adhesion complexes, primary cilia, mechanosensitive ion channels (TRP/Piezo), and the actin cytoskeleton–nucleus continuum, and are transduced into intracellular pathways with zone- and stage-specific effects, governing chondrocyte fate under physiological and osteoarthritic conditions. Mechanism-based anti-hypertrophic strategies include biomimetic scaffold design for focal defects, dynamic mechanical stimulation targeting early OA, and multimodal approaches integrating mechanical cues with biochemical factors, gene modulation, drug delivery, or cell-based therapies. Collectively, this review provides an integrated mechanobiological framework for understanding cartilage degeneration and highlights emerging opportunities for disease-modifying interventions targeting chondrocyte hypertrophy. Full article

Diacerein is known as a disease-modifying anti-inflammatory drug, primarily used for the treatment of osteoarthritis. Despite its therapeutic potential, the clinical use of diacerein is hindered by poor aqueous solubility, low bioavailability, liver issues, and gastrointestinal side effects, particularly diarrhea. To address these limitations, various innovative pharmaceutical formulation approaches have been explored, including physical modifications, chemical complexation, nanotechnology-based drug delivery systems, and synergistic combination therapies. This review highlights progress in formulation approaches aimed at enhancing the solubility and therapeutic profile of diacerein. Special emphasis is placed on lipid-based carriers, vesicular systems, pH-responsive hydrogels, and dissolving microneedles. Together, these strategies provide a comprehensive platform for the rational design of diacerein formulations, offering promising avenues to overcome its clinical limitations and improve patient outcomes. The insights presented here may also guide the development of more effective delivery systems for other poorly soluble anti-inflammatory agents. Full article

Recent technological breakthroughs have enabled multidimensional phenotyping, with unprecedented single-cell resolution and genome-wide coverage, across multiple osteoarthritis (OA)-relevant tissues, such as articular cartilage, synovium, infrapatellar fat pad, and subchondral bone. The majority of the single nucleotide variations (SNVs) that have been associated with OA are located in non-protein coding regions and confer risk for disease by altering the expression level, instead of the amino acid sequence of the gene product. These data have shaped the concept of OA as a polygenic disease, where genetic factors disrupt the chromatin landscape in disease-relevant cells, leading to aberrant expression of effector genes. Pharmacologic manipulation of the OA-driving epigenetic landscape has recently emerged as an attractive path for the development of disease-modifying drugs. Novel clustered regulatory interspaced short palindromic repeats (CRISPR)-based technologies provide opportunities for precise epigenetic editing at the desired genomic regions and may allow a targeted transcriptional regulation of disease-relevant genes in disease-relevant cells. The aim of the present narrative review is to summarize the emerging data on the role of epigenetic factors and chromatin structure as calibrators of the risk for developing OA and to discuss the opportunities and challenges arising from the use of chromatin landscape to guide drug discovery. Full article

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, synovial inflammation, and abnormal bone remodeling. Current therapies, such as NSAIDs, corticosteroids, and hyaluronic acid injections, primarily alleviate symptoms but often cause systemic side effects and fail to modify disease progression. Novel drug delivery systems (NDDS), including liposomes, polymer microspheres, nanoparticles, hydrogels, and biomimetic carriers, have emerged to enhance drug targeting, prolong retention, and reduce toxicity. These systems enable controlled release of anti-inflammatory, antioxidant, and gene therapies, improving therapeutic outcomes. However, challenges remain in biocompatibility, scalability, and clinical translation. Future efforts should focus on optimizing material design, functionality, and personalized approaches to facilitate the clinical application of NDDS for OA treatment. Full article

Osteoarthritis is a prevalent and disabling condition in companion dogs, yet existing treatments are primarily symptomatic and limited by safety concerns. EF-M2, a defined derivative of vitamin D-binding protein, selectively biases macrophages toward an anti-inflammatory phenotype in vitro. We conducted a randomised, double-blind, placebo-controlled trial (IMPAWS-OA-1) in 60 client-owned dogs with naturally occurring hip or elbow osteoarthritis. Animals were allocated to subcutaneous EF-M2 (0.1 µg/kg) given thrice weekly or twice weekly, or to saline placebo for four weeks, followed by four weeks off-drug. The primary endpoint was change in Canine Brief Pain Inventory–Pain Severity Score (CBPI-PSS) at Day 28. EF-M2 produced dose–frequency-dependent benefits: LS-mean ΔPSS was −2.11 for thrice weekly, −1.42 for twice weekly, and −0.54 for placebo (arm effect p < 0.001). Objective measures showed parallel improvements in peak vertical force and accelerometery. Serum biomarkers confirmed macrophage repolarisation (ARG1/iNOS ratio, IL-10 increase, TNF-α decrease), correlating with clinical response. Adverse events were infrequent and mild, with no excess over placebo. In conclusion, EF-M2 achieved clinically meaningful pain relief, functional gains, and biomarker shifts without safety signals, establishing first-in-species proof that targeted macrophage modulation may be a viable disease-modifying approach for canine osteoarthritis. Full article

Osteoarthritis (OA) remains a major contributor to pain and disability; however, the current management is largely reactive, focusing on symptoms rather than preventing irreversible cartilage loss. This review first examines the mechanistic foundations for pharmacological chondroprotection—illustrating how conventional agents, such as glucosamine sulfate and chondroitin sulfate, can potentially restore extracellular matrix (ECM) components, may attenuate catabolic enzyme activity, and might enhance joint lubrication—and explores the delivery challenges posed by avascular cartilage and synovial diffusion barriers. Subsequently, a practical “What–How–When” framework is introduced to guide community pharmacists in risk screening, DMOAD selection, chronotherapeutic dosing, safety monitoring, and lifestyle integration, as exemplified by the CHONDROMOVING infographic brochure designed for diverse health literacy levels. Building on these strategies, the P4–4P Chondroprotection Framework is proposed, integrating predictive risk profiling (physicians), preventive pharmacokinetic and chronotherapy optimization (pharmacists), personalized biomechanical interventions (physiotherapists), and participatory self-management (patients) into a unified, feedback-driven OA care model. To translate this framework into routine practice, I recommend the development of DMOAD-specific clinical guidelines, incorporation of chondroprotective chronotherapy and interprofessional collaboration into health-professional curricula, and establishment of multidisciplinary OA management pathways—supported by appropriate reimbursement structures, to support preventive, team-based management, and prioritization of large-scale randomized trials and real-world evidence studies to validate the long-term structural, functional, and quality of life benefits of synchronized DMOAD and exercise-timed interventions. This comprehensive, precision-driven paradigm aims to shift OA care from reactive palliation to true disease modification, preserving cartilage integrity and improving the quality of life for millions worldwide. Full article

Osteoarthritis (OA) is a multifactorial, degenerative joint disease that significantly impairs mobility and quality of life, especially among older adults. The growing aging population and increasing obesity rates are expected to increase the incidence and prevalence of OA. In the absence of Disease-Modifying Antirheumatic Drugs (DMARDs) for OA, current treatment strategies largely focus on symptom relief rather than disease modification. These symptomatic treatments often fail to account for the substantial inter-individual variability in drug response. Pharmacogenomics (PGx), the study of how genetic variation influences drug response, offers a promising approach to personalize OA therapy. This review explores the clinical and pharmacogenomic considerations of commonly used OA medications—acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine, and tramadol—focusing on gene–drug interactions that influence efficacy, safety, and metabolism. Evidence-based recommendations from the Clinical Pharmacogenetics Implementation Consortium guidelines are discussed, where applicable, to highlight actionable genetic variants in very important pharmacogenes such as CYP2D6, CYP2C9, and other important drug-metabolizing encoding genes such as CYP2E1 and UGT1A6. While PGx data are not currently embedded in OA clinical treatment guidelines, their integration into clinical practice may enhance therapeutic outcomes and minimize adverse drug events. This review underscores the potential of PGx as a clinical tool in OA pain management, paving the way toward truly personalized medicine. Full article

Osteoarthritis (OA) is a prevalent and disabling chronic disease, with knee OA being the most common form, affecting approximately 73% of individuals over 55 years. Traditional clinical assessments often fail to predict knee structural progression accurately, highlighting the need for improved prognostic methods. This perspective explores the complexity of stratifying knee OA patients based on rapid structural progression. It underscores the importance of such early identification to enable timely and personalized intervention and optimize disease-modifying OA drug clinical trial design, as many trial participants show minimal progression, complicating the assessment of treatment efficacy. We highlight the potential of machine learning (ML) and deep learning (DL) in overcoming this prognostic challenge, as these methodologies enhance classification/stratification capabilities by leveraging multidimensional data and capturing the intricate relationships between diverse features. These include panels of biochemical markers and imaging markers, such as those from magnetic resonance imaging (MRI), as integrating MRI data into ML/DL prognostic models enhances such prediction performance. These automated ML/DL models will offer a transformative approach to stratifying knee OA patients and represent a paradigm shift in disease management. Ultimately, ML/DL applications will not only improve patient outcomes but will also promote innovation in OA research, clinical practice, and therapeutics. Full article

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by low-grade inflammation, cartilage breakdown, and persistent pain. Despite its prevalence, current therapeutic strategies primarily focus on symptom management rather than modifying disease progression. Monoclonal antibodies and cytokine inhibitors targeting inflammatory pathways, including TNF-α and IL-1, have shown promise but remain limited by inconsistent efficacy and safety concerns. Long-acting biologic therapies—ranging from extended-release formulations, such as monoclonal antibodies and cytokine inhibitors, to gene therapy approaches—have emerged as promising strategies to enhance treatment durability and improve patient outcomes. Extracellular vesicles (EVs) have gained particular attention as a novel delivery platform due to their inherent stability, biocompatibility, and ability to transport therapeutic cargo, including biologics and immunomodulatory agents, directly to joint tissues. This review explores the evolving role of EVs in OA treatment, highlighting their ability to extend drug half-life, improve targeting, and modulate inflammatory responses. Additionally, strategies for EV engineering, including endogenous and exogenous cargo loading, genetic modifications, and biomaterial-based delivery systems, are discussed. Full article

ADAMTS-5 (aggrecanase-2) is a major metalloprotease involved in regulating the cartilage extracellular matrix. Due to its role in removing aggrecan in the progression of osteoarthritis (OA), ADAMTS-5 is often regarded as a potential therapeutic target for OA. Punicalagin (PCG), a polyphenolic ellagitannin found in pomegranate (Punica grunatum L.), and ellagic acid (EA), a hydrolytic metabolite of PCG, have been widely investigated as potential disease-modifying osteoarthritis drugs (DMOADs) due to their potent antioxidant and anti-inflammatory properties, but their interaction with ADAMTS-5 has yet to be determined. In this study, molecular docking simulations were used to predict enzyme–inhibitor binding interactions. The results suggest that both compounds may be able to bind within the active site via the formation of H bonds and interactions between the ligand’s aromatic rings and hydrophobic residue in the enzyme with inhibition constants of 183.3 µM and 1.13 µM for PCG and EA, respectively. Biochemical activity against recombinant human ADAMTS-5 was assessed using a dimethylmethylene blue-based assay to determine residual sulfated glycosaminoglycan (sGAG) in porcine articular cartilage. Although its loss could not be attributed to ADAMTS-5, sGAG was effectively persevered by PCG and EA. The potential conversion of PCG to EA by enzyme-catalyzed hydrolysis activity was then investigated using liquid chromatography–mass spectroscopy to determine the potential for the use of PCG and EA as a prodrug–proactive metabolite pair in the development of drug delivery systems to arthritic synovial joints. Full article

Osteoarthritis (OA) is the most prevalent rheumatologic disease and a leading cause of years lived with disability worldwide. There are no disease-modifying drugs available to treat it. This study aimed to evaluate the effect of a single dose of 100U botulinum neurotoxin-A (BoNT-A) in patients with early knee OA. We designed a single-arm preliminary clinical trial in patients diagnosed with knee OA (KOA) grades I and II. 45 Patients received a single dose of 100U IncobotulinumtoxinA in the retro-patellar bursa and received nutritional and physical rehabilitation indications. Patients were evaluated at baseline and at days 5, 30, 60, and 90 after injection. The primary outcome was the reduction in pain using the visual analog scale (VAS). Knee function was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). We assessed secondary adverse effects and measured muscular strength in every consultation. Descriptive endpoint summaries and a generalized linear random-effect model were used to evaluate changes in each follow-up time compared to baseline. IncobotulinumtoxinA treatment significantly (p < 0.001) reduced pain in all treated patients at day 90 compared to day 0. Patients showed a significant reduction in total WOMAC score (p < 0.001), from a mean baseline of 44.6 (95% CI; 41.4, 47.8) to 4.4 at day 90 (95% CI; 0.2, 0.3). Our results show that IncobotulinumtoxinA applied in the retro-patellar bursa is a safe and effective treatment for pain in patients with early-stage KOA, offering a potential alternative for symptomatic control in KOA. Full article

Osteoarthritis (OA) is a long-term degenerative condition of the joints, characterized by persistent inflammation, progressive cartilage breakdown, and impaired mitochondrial function. Recent studies have shown that hyperactivation of the mTORC1 pathway and metabolic reprogramming of chondrocytes contribute to disease progression. Nitazoxanide (NTZ), an oral antiparasitic agent approved by the Food and Drug Administration, has shown anti-inflammatory and mitochondrial protective effects in various disease situations; despite this, its application in osteoarthritis has yet to be fully investigated. Here, we assessed the therapeutic efficacy of NTZ using IL-1β-stimulated primary chondrocytes derived from patients with OA. NTZ substantially reduced the expression of proinflammatory cytokines and matrix metalloproteinases, restored mitochondrial membrane potential, and reduced mitochondrial reactive oxygen species levels. NTZ also effectively reversed IL-1β-induced glycolytic metabolic changes by inhibiting glucose uptake and GLUT1 expression. Mechanistically, NTZ inhibited the activation of the mTORC1 pathway and substantially increased AMPK phosphorylation. The siRNA-mediated AMPK knockdown negated NTZ-induced mitochondrial and metabolic improvements, suggesting that AMPK is a key upstream regulator of the protective actions of NTZ. NTZ can, therefore, effectively inhibit inflammatory metabolic reprogramming and mitochondrial dysfunction in OA chondrocytes through AMPK-dependent mTORC1 signaling inhibition, highlighting its potential as a disease-modifying therapy for OA. Full article

Background/Objectives: Inflammatory arthritides includes a range of joint disorders, such as osteoarthritis and rheumatoid arthritis, as well as inflammatory conditions like gout and lupus. This review investigates the pathophysiology, therapeutic challenges, and evolving treatment landscape of arthritis, with a particular focus on the clinical roles of rituximab, apremilast, and upadacitinib. Methods: A comprehensive analysis was undertaken to evaluate the current clinical application, therapeutic efficacy, and safety profiles of selected biosimilar and targeted synthetic disease-modifying antirheumatic drugs (bsDMARDs and tsDMARDs). This overview placed particular emphasis on three key agents—rituximab, apremilast, and upadacitinib—each exemplifying distinct immunomodulatory mechanisms. By focusing on these agents, the analysis highlights the evolving landscape of targeted therapies in rheumatology and underscores the importance of personalized treatment selection based on the disease phenotype, prior therapeutic responses, and comorbid conditions. Results: Rituximab, apremilast, and upadacitinib each present valuable therapeutic options for patients who have shown inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or nonsteroidal anti-inflammatory drugs (NSAIDs). Conclusions: Despite the complexity and heterogeneity of arthritis, agents like rituximab, apremilast, and upadacitinib have expanded the therapeutic possibilities in treating this disease and improved its management. Continued research is essential to optimize patient-specific treatment strategies and explore novel molecular targets. Full article

Background/Objectives: Arthritis encompasses a range of joint-related conditions, including osteoarthritis and rheumatoid arthritis, along with inflammatory diseases such as gout and lupus. This research study explores the underlying causes, challenges, and treatment options for arthritis, aiming to enhance the effectiveness of therapies. Methods: This research study evaluated current treatment strategies and examined the effectiveness of selected biological disease-modifying antirheumatic drugs (bDMARDs), i.e., abatacept, golimumab, and sarilumab, with a focus on emerging drug classes and their distinct mechanisms of action. Results: Biologic DMARDs like abatacept, golimumab, and sarilumab offer hopeful treatment alternatives for patients who fail to respond to conventional therapies. However, individual outcomes differ because of the disease’s complexity and the influence of accompanying health conditions. Conclusions: Treating arthritis continues to be challenging due to its numerous underlying causes and the varied ways in which patients respond to treatment. Although biologics and targeted therapies have brought progress, additional research is needed to identify new treatment targets and enhance patient results. Full article

Osteoarthritis (OA) is a chronic and debilitating joint disease characterized by progressive cartilage degeneration for which no definitive cure exists. Conventional management approaches often rely on fragmented and poorly coordinated pharmacological and non-pharmacological interventions that are inconsistently applied throughout the disease course. Persistent controversies regarding the clinical efficacy of chondroprotective agents, frequently highlighted by pharmacovigilance agencies, underscore the need for a structured evidence-based approach. Emerging evidence suggests that synchronizing pharmacotherapy and exercise regimens with circadian biology may optimize therapeutic outcomes by addressing early pathological processes, including low-grade inflammation, oxidative stress, and matrix degradation. Recognizing the influence of the chondrocyte clock on these processes, this study proposes a ‘prototype’ for a novel framework that leverages the circadian rhythm-aligned administration of traditional chondroprotective agents along with tailored, accessible exercise protocols to mitigate cartilage breakdown and support joint function. In addition, this model-based framework emphasizes the interdependence between cartilage chronobiology and time-of-day-dependent responses to exercise, where strategically timed joint activity enhances nutrient and waste exchange, mitigates mitochondrial dysfunction, supports cellular metabolism, and promotes tissue maintenance, whereas nighttime rest promotes cartilage rehydration and repair. This time-sensitive, comprehensive approach aims to slow OA progression, reduce structural damage, and delay invasive procedures, particularly in weight-bearing joints such as the knee and hip. However, significant challenges remain, including inter-individual variability in circadian rhythms, a lack of reliable biomarkers for pharmacotherapeutic monitoring, and limited clinical evidence supporting chronoexercise protocols. Future large-scale, longitudinal trials are critical to evaluate the efficacy and scalability of this rational integrative strategy, paving the way for a new era in OA management. Full article