Search Results (261)

Osteoarthritis (OA) is a multifactorial disease characterized by inflammation, extracellular matrix remodeling, and joint degeneration, and it still lacks disease-modifying treatments. Here, we applied an ex vivo OA model based on transwell co-cultures of cartilage and synovial membrane explants harvested from OA patients to compare the effects of adipose-derived stem/stromal cell (ASC) conditioned medium (CM) with dexamethasone (DEX), a clinically used corticosteroid. Explants were treated for 48 h with 100 nM DEX, CM derived from 5 × 10⁵ ASCs, or left untreated. Outcomes included gene and protein expression of key mediators, metalloprotease and aggrecanase activities, and nitric oxide release. DEX significantly reduced inflammatory markers (e.g., PTGS, IL-1β, and IDO) and VEGF expression in both tissues, while CM did not elicit consistent anti-inflammatory effects. Regarding matrix remodeling, both treatments reduced metalloprotease activity, with DEX modulating MMP3 and MMP13 expression in both tissues and CM reducing only MMP3 expression in cartilage while presenting high levels of TIMP-1. These results confirm the robustness of the model, demonstrated by reproducible responses to DEX and its high-throughput potential, and underscore the need for mechanistic studies to optimize novel biotherapeutics. Full article

Background/Objectives: Tenosynovial giant cell tumours (TGCT) are a group of mesenchymal tumours involving the synovium, bursae, and tendon sheaths, comprising two subtypes: nodular and diffuse. Although predominantly benign, diffuse forms can be locally aggressive, resulting in bone destruction. The pathogenesis of TGCTs is still poorly understood. The aim of this study was to systematically review the current literature on the factors, mechanisms, and markers involved in TGCT disease, focussing on their potential role in bone destruction. Methods: This systematic review was conducted using the PRISMA guidelines. A search was performed using PubMed, Scopus, and Cochrane Library, and all original scientific research into mechanisms/pathways/signalling involving TGCTs was included. Results: After the review process, 51 studies were included for data extraction. Extracted data included authorship, publication year, patient numbers and aetiology (nTGCT/dTGCT), demographics, investigative methods, and studied biological factors, mechanisms, and markers. Cross-tabulation of reported elements revealed 159 unique factors, with most appearing only once. Eight elements were reported five or more times: CSF1, CD68, Ki-67, MMP9, CD163, TRAP, TNF-α, and IL-1β. Although representing just 5% of all identified factors, these appeared in 69% of the included studies, highlighting their prominence in the literature. Conclusions: Apart from the well-known osteoclastogenesis factor CSF1, inflammatory cytokines (TNF-α and IL-1β) and monocyte–macrophage lineage makers (CD68, CD163) are signalling pathways key to TGCT disease progression and associated bone destruction. Full article

Osteoarthritis (OA) is increasingly conceptualized as a whole-joint disorder, in which pathological processes across articular cartilage, subchondral bone, synovium, and periarticular tissues are tightly interconnected. Within this context, miRNAs have emerged as central post-transcriptional regulators capable of integrating mechanical, inflammatory, and metabolic cues at the network level. In human OA, extensive evidence links miRNA dysregulation to cartilage catabolism, impaired stress adaptation, inter-tissue communication, and the emergence of extracellular and circulating miRNA (cmiRNA) signatures with diagnostic and translational relevance. In contrast, miRNA research in canine OA remains limited, despite dogs developing a naturally occurring form of the disease that closely mirrors human OA in clinical presentation, joint pathology, and biomechanical drivers. To date, only a single pilot study has systematically investigated miRNA expression in spontaneous canine OA, underscoring both the feasibility of miRNA profiling and the substantial gaps that persist in tissue validation and functional characterization. This review critically synthesizes miRNA-mediated regulatory mechanisms in human OA and leverages this evidence to define research priorities in canine OA, where experimental validation remains limited. By focusing on shared molecular contexts rather than assumed equivalence, the review defines a comparative framework highlighting cmiRNAs as promising non-invasive translational targets. Full article

Osteoarthritis (OA) is a prevalent degenerative joint disease which affects millions of patients across the globe. The infrapatellar fat pad (IPFP) harbors diverse cell types with intricate intercellular interactions. Its mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) possess significant biological functions and hold promising applications in regenerative medicine. IPFP exhibits active secretory capacity, releasing adipokines including leptin and adiponectin, along with various cytokines. Furthermore, it contains a rich neural network playing a crucial role in knee pain perception and sensation. Moreover, IPFP and synovium can be considered an integrated unit, exhibiting interactions both with each other and with cartilage. In imaging applications, IPFP is gaining widespread attention as an emerging biomarker. In clinical practice, the decision to resect or preserve IPFP remains a controversial topic. This article will review the latest research regarding the mechanism of IPFP in OA, and discuss its clinical applications, providing a theoretical basis for the prevention and treatment of OA. Full article

Difficult-to-treat (D2T) rheumatoid arthritis (RA) remains a major clinical challenge, affecting a significant proportion of patients who experience persistent symptoms despite multiple therapeutic regimens. This narrative review provides a comprehensive overview of potential molecular and cellular mechanisms that may underlie the D2T RA phenotype. We synthesize evidence across a broad biological landscape—the role of genetic and epigenetic factors, autoantibodies, and diverse immune cell subsets is detailed in the context of therapeutic resistance. Furthermore, we examine the potential role of synovial signatures and stromal cell-mediated pathways, which may drive chronicity independently of traditional immune targets. The review highlights the complex interplay of peripheral and central determinants that contribute to patient-reported outcomes such as pain. We also discuss comorbid conditions, environmental factors such as smoking and nutrition, and treatment-related factors relevant to the D2T population. By integrating these aspects, this work aims to facilitate better stratification and the identification of novel therapeutic targets for refractory disease. Full article

Imaging is the gold standard for diagnosing osteoarthritis (OA). However, it remains challenging to precisely assess OA in murine models. The aim of this study is to establish μCT-based geometric indices for assessing the disease severity of post-traumatic OA (PTOA) and age-related OA (AROA). Following medial meniscectomy (MMS) in adult C57BL/6 mice, distal femoral length remained unchanged, whereas its width increased significantly. As a result, distal femoral width-to-length ratio was markedly elevated at 4 and 8 weeks after MMS (1.33 ± 0.05 and 1.47 ± 0.1, n = 7 and 5 joints, respectively) compared to contralateral normal joints (1.19 ± 0.04, n = 9), yielding an area under the curve (AUC) of 1.0 (95% CI, 1.0–1.0). Similarly, the tibial secondary ossification center (IIOC) height decreased, whereas its width increased after MMS. Consequently, the tibial IIOC height-to-width ratio was significantly reduced at 4 and 8 weeks post-MMS (0.25 ± 0.02 and 0.24 ± 0.02, respectively) compared with a normal joint (0.304 ± 0.011), with an AUC of 1.0 (95% CI, 1.0–1.0). Bland–Altman analysis demonstrated strong interrater reproducibility, with intraclass correlation coefficients of 0.853 (95% CI, 0.681–0.936) for the femoral ratio and 0.887 (95% CI, 0.748–0.952) for the tibial ratio. Notably, these MMS-induced changes in femoral and tibial geometric indices were attenuated in mice with genetic deletion of GM-CSF, a key mediator of OA. Importantly, μCT-derived geometric indices were validated by histological analysis. Furthermore, increased distal femoral width-to-length ratio and reduced tibial IIOC height-to-width ratio were also observed in the knee joints of 28-month-old mice with AROA. In addition, an enlarged patella and a calcified synovium–capsule serve as a reference for AROA and PTOA. Collectively, μCT-based geometric indices are useful and easily quantifiable metrics for assessing disease severity and therapeutic response of PTOA and AROA models in murine. Of note is that the distal femoral and proximal tibial geometric indices were developed based on severe OA induced by MMS, and their applicability to mild OA requires further investigation. Full article

Background/Objectives: Tenosynovial giant cell tumor (TGCT), formerly known as pigmented villonodular tenosynovitis (PVNS), is a rare, benign, inflammatory mesenchymal neoplasm originating from the synovium of joints, bursae, or tendon sheaths. Although TGCT can affect any joint, the knee is the most commonly involved site, particularly in cases of diffuse-type TGCT. Bifocal or multifocal involvement is exceedingly uncommon. Methods: Herein, we present a case of localized TGCT with bilateral knee involvement in a 48-year-old female. Results: The patient underwent open arthrotomy with marginal excision of the localized lesions in both knees. Histology and immunohistochemistry staining conformed the diagnosis. At the five-year follow-up, the patient remains asymptomatic and free of recurrence. Conclusions: Given the rarity of bilateral TGCT, clinicians should maintain a high index of suspicion when evaluating patients presenting with bilateral knee pain and swelling and include TGCT in the differential diagnosis. To our knowledge, this represents the fifteenth reported case of bilateral knee TGCT in the literature. Full article

The diagnosis of crystal-induced arthritis is routinely established by synovial fluid analysis. However, a synovial effusion is not always present, fluid aspiration is not always possible or practical, and synovial fluid analysis is occasionally subject to false negative results. When there is a high suspicion of crystal-induced arthritis, but crystals are not identified in the synovial fluid, a biopsy of the synovium in search of crystals can assist in making a diagnosis. In this manuscript, we review the utility of ultrasound-guided needle biopsy of synovial tissue in the identification of crystal-induced arthritis, briefly describe the procedure, and recommend best practices for specimen handling and tissue processing. Full article

Joint acidosis is increasingly recognized as an important determinant of cellular behavior in osteoarthritis (OA). Declines in extracellular pH (pHe) occur across cartilage, meniscus, synovium, and subchondral bone, where they influence inflammation, matrix turnover, and pain. Among proton-sensing G protein-coupled receptors, GPR68 responds to the acidic pH range characteristic of human OA joints. The receptor is activated between pH 6.8 and 7.0, couples to Gq/PLC-MAPK, cAMP-CREB, G12/13-RhoA-ROCK signaling pathways, and is expressed most prominently in articular cartilage, with additional expression reported in synovium, bone, vasculature, and some neuronal populations. These pathways regulate transcriptional programs relevant to cartilage stress responses, inflammation, and matrix turnover. GPR68 expression is increased in human OA cartilage and aligns with regions of active matrix turnover. We previously reported that pharmacologic activation of GPR68 suppresses IL1β-induced MMP13 expression in human chondrocytes under acidic conditions, indicating that increased GPR68 expression may represent a microenvironment-responsive, potentially adaptive signaling response rather than a driver of cartilage degeneration. Evidence from intestinal, stromal, and vascular models demonstrates that GPR68 integrates pH changes with inflammatory and mechanical cues, providing mechanistic context, although these effects have not been directly established in most joint tissues. Small-molecule modulators, including the positive allosteric agonist Ogerin and the inhibitor Ogremorphin, illustrate the tractability of GPR68 as a drug target, although no GPR68-directed therapies have yet been evaluated in preclinical models of OA. Collectively, current data support GPR68 as a functionally relevant proton sensor within the acidic OA joint microenvironment. Full article

Rheumatoid arthritis (RA) is frequently accompanied by depression, a comorbidity arising from the interplay of chronic systemic inflammation, neuroimmune activation, oxidative stress, and dysregulation of the gut–brain axis. Increasing evidence suggests that nanomedicine offers unique opportunities for the integrated management of RA-associated depression by enabling precise modulation of both peripheral inflammation and central nervous system (CNS) pathology. This review outlines the biological mechanisms linking RA and depression—including cytokine cascades, mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and microbial metabolite imbalance—and highlights recent progress in nanocarrier platforms capable of dual-site intervention. Liposomes, polymeric nanoparticles (NPs), exosomes, inorganic nanozymes, and emerging carbon-based nanomaterials have demonstrated the ability to target inflamed synovium, reprogram macrophage phenotypes, traverse the blood–brain barrier (BBB), suppress microglial overactivation, enhance neuroplasticity, and restore gut microbial homeostasis. Furthermore, stimulus-responsive nanoplatforms activated by ROS, pH, enzymes, or hypoxia provide spatiotemporally controlled drug release, thereby improving therapeutic precision. Finally, we discuss integrative designs such as dual-targeting nanomedicines, co-delivery systems, and microbiota-modulating nano-interventions, which offer promising strategies for the comprehensive treatment of RA-associated depression. This review aims to provide mechanistic insights and design principles to guide the development of next-generation nanomedicine for coordinated systemic-central modulation in RA comorbidity. Full article

Osteoarthritis (OA) is a common and debilitating degenerative joint disease associated with aging and more common among women. OA is a disease that affects many parts of the joint, including cartilage, subchondral bone, and the synovium. Although the exact cause of OA is still under investigation, major factors include dysregulation of inflammatory cytokines and loss of function of mesenchymal stem cells (MSCs). Unfortunately, current treatments for OA are limited to symptomatic management, including nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular injections such as hyaluronic acid (or cortisol), physical therapy, and surgical intervention, none of which can affect disease progression or provide permanent solutions. Currently there is no FDA approved treatment that can address the molecular basis of OA, although some promising candidates include bone marrow-derived MSC injection, adipose-derived MSC injection, pulsed electromagnetic field (PEMF), TissueGene-C, and CK2.1. Full article

Background/Objectives: Chronic synovitis is a hallmark of osteoarthritis (OA) progression, driving cartilage degradation via inflammatory mediators. While the MAPK signaling pathway is implicated in OA pathogenesis its activation patterns in hip synovium remain poorly characterized, and regional differences within the synovial membrane have not been systematically examined. This research aims to determine the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and the Epidermal Growth Factor Receptor (EGFR) in the MAPK signaling pathway in the synovial membrane of osteoarthritic hips. Methods: We compared synovial immunofluorescence expression of the aforementioned proteins in a control (CTRL) group of subjects with femoral neck fractures and a group with hip OA. Results: Higher ERK1/2 immunoexpression was detected in the intima compared with the subintima in the CTRL group (p < 0.05), and a similar distribution was observed in the OA group (p < 0.0001). The intima of the OA group exhibited a considerably greater area percentage of positive signal than the intima of the CTRL group (p < 0.01). In all groups examined, we observed that p38 MAPK expression was markedly more positive in the intima than in the subintima (p < 0.0001), but without statistically significant differences between groups. JNK and EGFR immunoexpression were higher in the intima than in the subintima across all analyzed groups, but the difference did not reach statistical significance (p > 0.05). No differences in the expression of these two markers were detected between the CTRL and OA groups (p > 0.05). Differential analysis of the GEO dataset revealed no significant differences in expression between the OA and CTRL groups in the expression of MAPK1, MAPK3, MAPK8, MAPK9, MAPK10, and MAPK11. EGFR was significantly elevated in OA compared to CTRLs in the differential analysis of the GEO dataset. Conclusions: This study provides the first comprehensive analysis of MAPK pathway activation in hip OA synovium, revealing ERK1/2 as a key player with region-specific upregulation in the synovial intima. Combined with elevated EGFR expression, these findings suggest potential therapeutic targets for hip OA synovitis. The discordance between protein and mRNA levels for ERK1/2 indicates post-transcriptional regulation, warranting further investigation into phosphorylation status and functional activation. Our results support the development of targeted interventions for hip OA, a condition with limited treatment options beyond joint replacement. Full article

The pathogenesis of knee osteoarthritis (OA) is multifaceted and involves the complete joint microenvironment. Despite beneficial evidence of curcumin, the mechanistic insights of nanoemulsified curcumin (n-Cur) delivery to the knee-OA microenvironment are limited. The study aimed to establish localized delivery of curcumin nanoemulsion in the knee joint of OA rats and to examine detailed histopathological changes. n-Cur was prepared using a neutral dietary oil and a surfactant. Adult (5 mo) male SD rats were intra-articularly delivered 40 mg/mL of monoiodoacetate (MIA) to induce OA in the left knee and further treated with n-Cur (30 mg/mL). The effect of n-Cur on macrophage recruitment was evaluated using a co-culture model of CHON 001 and RAW 264.7 cells. In the MIA model, localized delivery of n-Cur significantly reduced knee joint edema and joint space narrowing in the target site. Curcumin ameliorated cartilage degeneration by reducing fibrillation, hypocellularity, and restoring matrix proteoglycan, as evidenced by histology. Reduced synovial inflammation displays the effect of curcumin on the synovium, possibly by lowering the recruitment of macrophages in chemoattractant-stimulated chondrocytes. Thus, curcumin nanoemulsion can act as a chondroprotective agent, modulating the OA microenvironment by reducing joint edema, synovial inflammation, and oxidative stress in the OA model. Full article

Osteoarthritis (OA), the most prevalent form of arthropathy, is characterized by progressive degradation of cartilage, synovial inflammation, and other pathological changes that gradually affect the entire joint. Once regarded as a purely degenerative disease with minimal immune involvement, recent evidence reveals that chronic low-grade inflammation, insidiously fueled by the destructive crosstalk between cartilage and synovium, plays a key role in OA pathophysiology. Among the immune cells involved, eosinophils have emerged as unexpected yet significant contributors, exhibiting both pro-inflammatory and immunoregulatory properties. Traditionally associated with allergic responses and antiparasitic defense, eosinophils can also secrete anti-inflammatory cytokines along with specialized pro-resolving lipid mediators (SPMs) that promote macrophage polarization toward reparative M2 phenotypes. Eosinophils may sustain inflammation or, conversely, act as “silent modulators” that subtly shape the immune microenvironment and support tissue homeostasis. This immunological plasticity positions them at the intersection of joint damage and repair. This article explores emerging evidence on eosinophil activity in OA, emphasizing their dual nature and potential as therapeutic targets to shift the joint milieu from a pro-inflammatory state toward resolution. Understanding eosinophil-mediated pathways may pave the way for novel strategies to reduce synovial inflammation, preserve cartilage integrity, and improve clinical outcomes. Full article

Interleukin 17 (IL-17) is a crucial mediator at the interface of periodontal dysbiosis and host immunity. This review synthesizes current evidence on IL-17 in periodontitis (PD), its systemic connections, and the role of IL-17 gene variants. Clinical and experimental studies show that IL-17 rises in periodontal disease and is associated with the severity of PD via action on epithelial, stromal and osteoblastic cells to promote chemokine release, neutrophil recruitment, cyclooxygenase 2 and prostaglandin E2 synthesis, RANKL expression, osteoclastogenesis, and matrix metalloproteinase activity. Periodontopathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans pre-activate the local inflammation-maintaining Th17 response. There is converging evidence linking IL-17-centered signaling with rheumatoid arthritis, diabetes mellitus, and psoriasis in favor of a shared inflammatory network in barrier tissues and synovium. Despite these associations, IL-17 biology is contextually determined with mucosal defense and bone homeostatic roles that caution against unidimensional explanations. Evidence on IL-17A and IL-17F polymorphisms is still heterogeneous across populations with modest and variable risk associations with PD. Clinically, IL-17 in gingival crevicular fluid, saliva, or serum is a potential monitoring biomarker when utilized along with conventional indices. Therapeutically, periodontal therapy that reduces microbial burden may inhibit IL-17 function, and IL-17-targeted therapy has to balance potential benefit to inflammation and bone resorption against safety in oral tissues. The following research must utilize harmonized case definitions, standardized sampling, and multiethnic cohorts, and it must include multiomics to be able to differentiate between causal and compensatory IL-17 signals. Full article