Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage degradation, osteophyte formation, and joint dysfunction, significantly impairing the quality of life in the elderly population. Recently, RNA modifications, as a dynamic and reversible epigenetic modification, have emerged as critical players in the onset and progression of OA. This review systematically summarizes the major types of RNA modifications involved in OA, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), and 7-methylguanosine (m7G), and explores their roles in regulating chondrocyte autophagy, inflammatory responses, and key signaling pathways. with a primary focus on RNA methylation. Special emphasis is placed on the dynamic regulatory functions of key methyltransferases (e.g., METTL3, FTO, WTAP) and their potential contributions to OA pathogenesis. Furthermore, we address current research hotspots and controversies in the field, proposing future research directions, such as leveraging single-cell sequencing to decipher dynamic RNA modification changes during OA progression and uncovering the cooperative networks among various RNA modifications. Advancing our understanding of the biological roles and mechanisms of RNA modifications holds promise for innovative strategies in the early diagnosis, disease stratification, and targeted therapy of OA.

Osteoarthritis (OA) is characterized by cartilage degradation, synovial inflammation, subchondral bone remodeling, and osteophyte formation, leading to chronic pain and impaired mobility. Chondrocyte senescence, inflammation, and hypertrophic differentiation critically contribute to OA progression. Integrated analysis of four GEO datasets identified SERPINF1 as a consistently upregulated gene in both human and animal OA samples. Histopathological and immunohistochemical analyses confirmed increased SERPINF1 in OA cartilage, where chondrocytes showed elevated SERPINF1 protein alongside reduced aggrecan expression. Functional studies revealed that SERPINF1 knockdown in OA chondrocytes diminished senescence markers (p21, p16, p53) while increasing Lamin B1, and reduced levels of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). Conversely, overexpression of SERPINF1 in normal chondrocytes induced senescence and increased inflammatory mediator expression, accompanied by altered extracellular matrix metabolism and hypertrophy marker expression. Mechanistic analysis further implicated the TNF-α/NF-κB signaling pathway in mediating these effects. In a destabilization of the medial meniscus (DMM) mouse model, intra-articular SERPINF1 knockdown attenuated cartilage destruction, reduced senescence and inflammatory markers, and restored ECM integrity. Collectively, these findings demonstrate that SERPINF1 promotes OA progression by exacerbating chondrocyte senescence, inflammation, and hypertrophy, suggesting that targeting SERPINF1 may offer a novel therapeutic strategy for OA.

Chondrogenic progenitor cells (CPCs) in the articular cartilage of knee osteoarthritis (OA) patients exhibit cellular senescence and its associated secretory phenotype (SASP). We hypothesized that the senescence of CPCs can be suppressed using natural compounds. This study aimed to evaluate the senotherapeutic effects of fisetin and resveratrol to suppress the cellular senescence in CPCs. In vitro, pre-treatment of CPCs with increasing doses of fisetin and resveratrol (5μM-100μM) were non-cytotoxic, decreased the senescence index and dampened the expression of cellular senescence markers, p53 and p38MAPK. Additionally, SASP-related genes and proteins (MMP-9, MMP13) and inflammatory mediators (IL-1β, TGF-β, and IL-6) were downregulated. Further, in silico analysis confirmed the high binding affinity of these natural drugs to OA-related proteins. Overall, fisetin and resveratrol dampened the senescence of CPCs by downregulating the p53 effector protein and effectively reducing the SASP. From this study, natural compound candidates proved to be potential drug candidates that suppress senescence via p53.

Osteoarthritis (OA) is a serious health issue that lacks a totally effective treatment. In light of the critical need for alternative therapies to halt osteoarthritis and its progress, This study explores the potential of Lolium perenne as a treatment for osteoarthritis for the first time. The research evaluates the plant's protective effects against monosodium iodoacetate (MIA)-induced OA in rats. 24 rats were assigned into 4 groups, group I (sham control), group II (OA), group III (dichloromethane fraction (FrII) + OA), and group IV (ethyl acetate fraction (FrIII) + OA). For 21 days, the samples were given orally at a dose of 40 mg/kg. The obtained results indicated all treatment groups showed a significant decrease in the severity of articular cartilage degradation and in the concentration of Interleukin-1 beta (IL-1β) and Tumor necrosis factor alpha (TNF-α) cytokines compared to the OA-induced group Moreover, eight structurally varied metabolites were isolated and identified from the FrII and FrIII fractions derived from the methanol extract of the aerial part of L. perenne, which were linked with pro-inflammatory cytokines in the computational docking investigation. Interestingly, salcolin B (2b) and calquiquelignan E (4) isolated from FrII fraction, showed prevalent activity for the two tested receptors [salcolin B, IL-1β (-6.7354 kcal/mol) and calquiquelignan E, TNF-α (-6.2038 kcal/mol)] compared to the reference flurbiprofen drug. Finally, the frontier candidates against IL-1β and TNF-α receptors simulated at 100 ns and the MM-GBSA calculations confirming the docking results. These findings highlight L. perenne's potential as a natural therapeutic for OA.

Temporomandibular joint osteoarthritis (TMJ-OA) is painful and causes masticatory dysfunction, but current treatment is limited to symptom relief due to an incomplete appreciation of aetiology. Herein, we develop morphological and histological methods for quantitative evaluation of TMJ-OA severity and examine whether STR/Ort mice, which are genetically predisposed to spontaneous knee OA, exhibit protection against TMJ-OA upon genetic gain-of-function modification of an aggrecanase-selective mutant of tissue inhibitor of metalloproteinase (TIMP)-3.

We established morphological changes in mandibular condylar head adapted from human TMJ-OA criteria, and developed and verified the utility of TMJ-OA histological damage scoring adapted from the OARSI system. Mutant TIMP3 containing an extra alanine at the N-Terminus ([-1A] TIMP-3 was overexpressed in STR/Ort and CBA mice. Morphological changes in mandibular condyle and TMJ cartilage degradation were evaluated and quantified using micro-CT and histology in mice aged 10, 20 and 40 weeks.

Whilst no evidence of TMJ-OA was observed in STR/Ort mice aged 10 weeks, bone erosion and osteophyte formation appeared in the mandibular condyle by 20 weeks, with remarkable deformity and bone resorption at 40 weeks in STR/Ort, but not the parental CBA strain. TMJ-OA was less severe in 40 week-old [-1A]TIMP-3 overexpressing STR/Ort and CBA compared to wild-type mice.

Using our new mouse TMJ-OA scoring system we have found that OA affects joints other than the knee in the STR/Ort strain. Genetic gain-of-function modification of STR/Ort mice with an aggrecanase-selective mutant of tissue inhibitor of metalloproteinase (TIMP)-3 also affords in vivo chondroprotection against this TMJ-OA.

Osteoarthritis (OA) is a musculoskeletal degenerative disease characterized by alterations in cartilage and subchondral bone leading to impaired joint function. OA disproportionally affects females more than males, yet the molecular mechanisms underlying these biological sex differences remain elusive. Current therapeutic strategies to halt the progression of OA are still lacking, in part due to the limited predictive potential of standard models which often do not account for sex disparities. Herein, an organ-on-chip microfluidic platform was developed to model the osteochondral unit, composed of adjacent bone and cartilage culture chambers, and capture sex-specific hallmarks of OA. Sex-stratified human primary chondrocytes and osteoblasts were compartmentalized within biomimetic hydrogels emulating the bone-cartilage interface, which were subjected to inflammatory triggers to mimic the onset of OA. We confirmed that interleukin-1β and Tumor Necrosis Factor-α stimulation triggered upregulation of pro-inflammatory cytokines and matrix metalloproteinases related genes in all donors, with marginal trends for increased expression in female cells. In addition, metabolic labeling coupled with confocal imaging revealed that inflammatory stimulation modulated extracellular matrix deposition by human chondrocytes in a sex-specific fashion. Not only matrix deposition but also matrix remodeling was altered upon inflammation, leading to a significant reduction in matrix stiffness in both cartilage and bone compartments. Overall, sex-stratified osteochondral unit on-chips offer novel insights into sex-specific cellular responses to inflammatory insults, demonstrating the importance of incorporating sex stratification in emergent organ-on-chip models. Thus, this platform provides a physiologically relevant 3D microenvironment to further investigate sex-specific drivers of OA, paving the way for targeted therapies.

Objectivesα2-Macroglobulin (A2M) can prevent cartilage degeneration by blocking many types of cartilage-degrading enzymes, but the mechanism remains to be clarified. This study aimed to test that A2M protects against cartilage degeneration by promoting chondrocyte proliferation and cartilage matrix synthesis via inducing proliferating cell nuclear antigen (PCNA).DesignThe cartilage degeneration of the anterior cruciate ligament transection (ACLT) model was evaluated by Safranin O-fast green staining, and articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. The chondrocyte proliferation was detected by 5-Bromodeoxyuridinc (BrdU), MTT, and Cell Counting Kit-8 (CCK8) methods. The chondrocyte apoptosis was detected by lactate dehydrogenase (LDH) assay and Annexin PI staining with the flow cytometer. The glycosaminoglycan (sGAG) and aggrecan in culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to analyze the type II collagen and aggrecan mRNA expression. The PCNA protein expression was analyzed by western blot and immunofluorescent staining.ResultsA2M can attenuate cartilage degeneration in ACLT rats. The OARSI scores for cartilage degeneration in the A2M group were lower than those in the phosphate-buffered saline (PBS) group. A2M can promote chondrocyte proliferation and inhibit chondrocyte apoptosis, promote the cartilage matrix synthesis in chondrocytes (type II collagen and aggrecan), and culture supernatant (sGAG and aggrecan). At the same time, it also up-regulated the PCNA protein expression in chondrocytes.ConclusionsA2M can promote chondrocyte proliferation and cartilage matrix synthesis via inducing PCNA expression.

This study investigated the effects of a high-impact exercise regimen compared with a reference group on systemic cytokine levels in patients with mild knee osteoarthritis (OA). Furthermore, associations between cytokines and magnetic resonance imaging (MRI) transverse relaxation time (T2) mapping and metabolic equivalent task hours (MET-hours) during leisure-time physical activity (LTPA) were assessed.

In this secondary analysis, 73 postmenopausal women aged 50-65 years with mild knee OA were randomized to a 12-month high-impact aerobic/step aerobics training group (n ​= ​35) or a non-training reference group (n ​= ​38). The serum cytokine levels, including interleukin-1 alpha (IL-1α), IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), were determined via multiplex cytokine assays. The cartilage structure of the medial tibial condyle was assessed by MRI T2 mapping. The primary outcome was between-group differences in cytokine level changes.

After a 12-month follow-up, no significant differences in cytokine level changes were found between the groups. In the intervention group, 12-month changes in TNF-α levels were associated with changes in medial tibial condyle T2. In the reference group, 12-month changes in IL-10 levels were associated with changes in medial tibial condyle T2 and the number of weekly LTPA MET-hours.

A progressive high-impact exercise regimen did not affect systemic cytokine levels compared to the reference group and could therefore offer a possible mode of exercise for postmenopausal women with mild knee OA.

ISRCTN58314639.

Shufeng Jiedu Capsules (SFJDC) is a traditional Chinese patent medicine comprising eight traditional Chinese medicines (TCM). SFJDC is known for its anti-inflammatory and antipyretic effects and is mainly used in clinics to treat upper respiratory tract infections. Currently, studies on the active ingredients of the SFJDC all focus on small-molecule compounds. In contrast, bio-macromolecules, such as the anti-inflammatory activities of polysaccharides in SFJDC, have not been studied, and the composition of the polysaccharides in SFJDC is also unclear.

This study aimed to isolate active polysaccharides from Shufeng Jiedu capsules and determine their structural properties and anti-inflammatory activities.

The polysaccharides with different molecular weights were prepared by organic solvent extraction, alcohol precipitation, dialysis, and cross-flow ultrafiltration. The structural characterization of polysaccharides was clarified by high-performance size exclusion chromatography (HPGPC), ion chromatography (IC), and Fourier transform infrared spectroscopy (FT-IR). Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR) assay were used to investigate the anti-inflammatory effects of polysaccharides on Lipopolysaccharides (LPS)-stimulated RAW264.7 cells. The in vivo study was employed on the CuSO4-induced and LPS-stimulated zebrafish inflammatory models, and the survival analysis, observation of neutrophil migration, hematoxylin-eosin (H&E) staining, and qRT-PCR assays were used to investigate the in vivo anti-inflammatory effect of polysaccharides.

The crude polysaccharides SFJDC-CP were obtained from the mixed aqueous extract of SFJDC with a yield of 38.72 %. Both SFJDC and SFJDC-CP dose-dependently inhibited the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in LPS-stimulated RAW264.7 cells, and SFJDC-CP was more effective at a lower dosage. SFJDC-CP was further separated into three fractions, SFJDC-CP1-CP3, by cross-flow ultrafiltration apparatus with nominal molecular weight cut-offs of 100 kDa, 50 kDa, and 10 kDa membrane cassettes, and the yields were approximately 58.19 %, 10.88 %, and 30.94 %, respectively. The MWs of the SFJDC-CP and its SFJDC-CP1-CP3 were 35.7 kDa, 149.1 kDa, 34.5 kDa, and 15.1 kDa, respectively. The four polysaccharides were composed of rhamnose, arabinose, galactose, glucose, and galacturonic acid in different molar ratios. Non-toxic concentrations of the four polysaccharides ranged from 12.5 to 200 μg/mL. The four polysaccharides significantly reduced the mRNA expression levels and release of IL-1β, IL-6, and TNF-α (P < 0.0001) in LPS-stimulated RAW264.7 cells. Polysaccharides also decreased inflammatory cell infiltration and neutrophil migration (P < 0.05 or P < 0.001) in both CuSO4-induced and LPS-microinjected zebrafish inflammatory models. Additionally, they effectively inhibited the mRNA levels of IL-6 and TNF-α in LPS-infected zebrafish (P < 0.01 or P < 0.001).

Polysaccharides isolated from Shufeng Jiedu capsules have demonstrated anti-inflammatory effects on LPS-stimulated RAW264.7 cells and zebrafish inflammatory models. This study provided preliminary evidence that polysaccharides are one of the main anti-inflammatory ingredients of Shufeng Jiedu capsules. Additionally, it may provide valuable perspectives for investigating polysaccharides in other TCM formulations, particularly those obtained through aqueous extraction methods.

Osteoarthritis is the most prevalent age-related degenerative joint disease and is closely linked to obesity. However, the underlying mechanisms remain unclear. Here we show that altered lipid metabolism in chondrocytes, particularly enhanced fatty acid oxidation (FAO), contributes to osteoarthritis progression. Excessive FAO causes acetyl-CoA accumulation, thereby altering protein-acetylation profiles, where the core FAO enzyme HADHA is hyperacetylated and activated, reciprocally boosting FAO activity and exacerbating OA progression. Mechanistically, elevated FAO reduces AMPK activity, impairs SOX9 phosphorylation, and ultimately promotes its ubiquitination-mediated degradation. Additionally, acetyl-CoA orchestrates epigenetic modulation, affecting multiple cellular processes critical for osteoarthritis pathogenesis, including the transcriptional activation of MMP13 and ADAMTS7. Cartilage-targeted delivery of trimetazidine, an FAO inhibitor and AMPK activator, demonstrates superior efficacy in a mouse model of metabolism-associated post-traumatic osteoarthritis. These findings suggest that targeting chondrocyte-lipid metabolism may offer new therapeutic strategies for osteoarthritis.

Branched-chain amino acids (BCAA) metabolism is significantly associated with osteoarthritis (OA), but the specific mechanism of BCAA related genes (BCAA-RGs) in OA is still unclear. Therefore, this research intended to identify potential biomarkers and mechanisms of action of BCAA-RGs in OA tissues.

Differential genes were obtained from the Gene Expression Omnibus (GEO) database and intersections were taken with BCAA-RGs to identify candidate genes. The underlying mechanisms were revealed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, by combining three machine learning algorithms to identify genes with highly correlated OA features. In addition, created diagnostic maps and subject Receiver operating characteristic curves (ROCs) to assess the ability of the signature genes to diagnose OA and to predict their possible roles in molecular regulatory network axes and molecular signaling pathways.

Eight candidate genes were acquired by intersecting 4,178 DEGs and 14 BCAA-RGs. Subsequently, five candidate biomarkers were obtained, namely SLC3A2, SLC7A5, SLC43A2, SLC43A1, and SLC7A7. Importantly, SLC3A2 and SLC7A5 were validated by validation set and qRT-PCR. Furthermore, the nomogram constructed by SLC3A2 and SLC7A5 exhibited excellent accuracy in predicting the incidence of OA. The enrichment results demonstrated that SLC3A2 and SLC7A5 were significantly enriched in ribosome, insulin signaling pathway, olfactory transduction, etc. Meanwhile, we also found XIST regulated SLC7A5 through hsa-miR-30e-5p, and regulated SLC3A2 through hsa-miR-7-5p.OIP5-AS1 regulated SLC7A5 and SLC3A2 through hsa-miR-7-5p. By the way, 150 drugs were identified, including Acetaminophen and Acrylamide, which exhibited simultaneous targeting of these two biomarkers.

Based on bioinformatics, SLC3A2 and SLC7A5 were identified as biomarkers related to BCAA in OA, which may provide a new reference for the treatment and diagnosis of OA patients.

Osteoarthritis (OA) is a multifactorial degenerative disease involved subchondral bone remodeling, cartilage destruction and synovium inflammation. While receptor activator of nuclear factor-κB ligand (RANKL), a tumor necrosis factor (TNF) superfamily protein, is the critical regulator in bone metabolism associated with subchondral bone resorption, TNF-α is also an important inflammatory factor involved in the OA inflammation and cartilage destruction. Based on previous compound Y1599, we identified a novel tetrahydro-β-carboline derivative Y2641 with both RANKL and TNF-α inhibition in this study. Y2641 exhibited potent RANKL-induced osteoclastogenic inhibition (IC50 = 109.1 nM), and had anti-inflammatory and cartilage destruction inhibiting effects at 10 μM with low cytotoxicity. SPR assays demonstrated the binding affinity of Y2641 to RANKL (Kd = 3.984 μM) and TNF-α (Kd = 18.59 μM). In vivo assay further revealed the disease-modifying effects of Y2641 in OA rats, establishing Y2641 as a promising lead compound for the development of disease-modifying osteoarthritis drugs.

Knee osteoarthritis (OA) is a common degenerative joint disease that affects millions of people worldwide. Inflammation is one of the key pathogenic factors of knee OA. However, the causal relationship between immune cells and knee OA development remains unclear. Herein, we used Mendelian randomization (MR) analysis to evaluate causal relationship between 731 immune cells and knee OA. Several methods were applied to ensure the robustness of our results, including inverse-variance weighted (IVW), simple mode, weighted median, weighted mode, and MR-Egger. We found that 23 immune cell phenotypes were causally associated with knee OA (P < 0.05), including various subpopulations of B cells, T cells, TBNK (T cells, B cells, Natural Killer cells) and monocytes, which was confirmed by heterogeneity, sensitivity, and pleiotropy tests. B cells had dominant effects on OA development, and specifically, our findings suggest that BAFF-R in IgD + CD38- unswitched memory B cells may have a protective role, whereas CD25 in IgD + CD24 + B cells appears to be associated with increased risk, pending further validation. Moreover, a higher population of regulatory T (Treg) cells indicated a higher risk of OA and reversely, OA could induce Treg differentiation. Collectively, our study identified several immune cells that were closely related to OA development, which provided novel insights into the pathogenesis of OA and therapeutic targets for OA treatment.

In the paper we presented the review of mathematical and numerical models of osteoarthritis (OA). As angiogenesis seems to be the most principal factor in OA mathematical and numerical modelling, we focused on the models that consider the process. The spectrum of the presented models is wide. They were divided in the scale of the simulated phenomena, i.e., micro- or macro-scale. A part of them considers only damage of tissue without paying attention to its remodeling. Others consider loss of tissue, new tissue formulation and remodeling of bone, both in micro- and macro-scale. What is worth mentioning is that most of the models were confirmed by comparing results to data available in literature. Only a few of them were experimentally validated. As the conclusion, we stated that the most accurate models are those that take into consideration mechanical stimulation, biological signaling and their nonlocal effects. Also, an important feature of an OA model is the ability to adapt it to various cases to be able to simulate OA in any joint.

Osteoarthritis (OA) is a widespread musculoskeletal disorder affecting ≈600 million people globally, and small interfering RNA (siRNA) therapy shows potential in targeting OA progression. However, the efficient and targeted delivery of siRNA remains a major challenge due to issues with tissue specificity and degradation in vivo. In this study, A DNA origami-based chondrocyte-targeted delivery system (OCS) is designed for siRNA delivery to OA-affected cartilage. The DNA origami is engineered to load with siRNA targeting signal transducer and activator of transcription 3 (Stat3), a key regulator of inflammation and cartilage degradation, and is functionalized with anti-CD44 aptamers for selective targeting of OA chondrocytes. In vitro, the DNA origami system effectively delivers siRNA to diseased chondrocytes, silencing matrix metalloproteinases expression and reducing inflammation. In OA rat models, it preserves cartilage integrity, promotes regeneration, and mitigates ECM degradation without evident side effects. These findings highlight DNA origami as a promising platform for siRNA-based OA therapy, offering a promising solution to the challenges of targeted and efficient siRNA delivery.

Osteoarthritis (OA) affects more than 250 million people worldwide, with current therapies focused primarily on symptom management rather than addressing underlying disease mechanisms. Here, MHTCK, a novel biomimetic nanoplatform is presented that uniquely integrates CeO₂ nanozymes with the anti-inflammatory peptide KAFAK through the fusion of a macrophage-synoviocyte membrane coating. Physicochemical characterization reveals that MHTCK maintains nanostability with a size of ≈ 200 nm and a surface charge of -30 mV. Compared with conventional antioxidant nanoparticles, the platform demonstrated superior cellular uptake in synoviocytes (2.8-fold), chondrocytes (3.2-fold), and macrophages (4.1-fold). In vitro studies revealed that MHTCK effectively scavenged multiple ROS species by targeting mitochondria while preserving mitochondrial function as evidenced by the maintenance of ATP production, and promotion of M2 macrophage polarization. The biomimetic membrane coating enabled prolonged joint retention of up to 10 days postinjection through specific tissue-targeting mechanisms, significantly improving pain thresholds and cartilage preservation in an OA rat model. This work demonstrates how rational integration of nanozyme technology with peptide therapeutics in a biomimetic delivery system can effectively modulate both oxidative stress and inflammation in OA, while maintaining cellular bioenergetics, providing new insights for developing targeted nanotherapeutics for inflammatory joint diseases.

Electroacupuncture (EA) has been shown to be effective in the treatment of knee osteoarthritis (KOA); however, its underlying mechanism remains unclear.

40 KOA model rats were divided into control, untreated model, EA-treated model and celecoxib-treated model groups (n=10 each). Articular cartilage of the knee joint was stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS) and Alcian blue (AB)-PAS, and Moran/Mankin scores were used to evaluate articular cartilage injury across groups. Moreover, toll-like receptor (TLR)4/nuclear factor (NF)-κB pathway (TN-P)-related protein levels in the articular cartilage were detected using Western blotting. Oxidative stress and inflammatory biomarkers in the synovial fluid were measured by enzyme-linked immunosorbent assay (ELISA). MicroRNA (miRNA/miR) expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR).

Compared with the control group, Moran scores increased and Mankin scores decreased in the KOA model rats. In addition, compared with those in the control group, levels of superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and interleukin (IL)-10 were significantly decreased, while levels of IL-1β, IL-6, tumor necrosis factor (TNF)-α, malondialdehyde (MDA) and nitric oxide (NO) were significantly increased, in the synovial fluid of the KOA model group. Protein levels of TLR4, anti-myeloid differentiation primary response protein 88 (MyD88) and p65 NF-κB phosphorylation were significantly increased in the articular cartilage of the KOA model group. EA and celecoxib treatment reversed the trends of these protein levels. Moreover, expression of miR-15a/127/140/146a/216a-5p and miR-27a-3p in the articular cartilage were markedly increased in KOA rats, while EA and celecoxib treatment reduced their expression.

EA reduces inflammation, oxidative stress and cartilage damage in KOA model rats, likely through regulation of the miRNA/TLR4/NF-κB pathway.

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by the progressive breakdown of cartilage, leading to pain, inflammation, and reduced joint function. There are many variations of conventional therapies that exist, however, none proven to halt or reverse cartilage degradation. Chitosan, a biocompatible and biodegradable polysaccharide, has emerged as a promising candidate in OA treatment due to its chondroprotective properties, and ability to enhance chondrocyte proliferation and suppress inflammatory mediators. Recent advancements in nanotechnology have led to the development of chitosan nanoparticles (NPs), which offer a novel and effective approach for addressing the limitations associated with standard chitosan formulations, such as poor solubility and limited tissue penetration. Chitosan NPs have demonstrated superior bioavailability, sustained drug release, and targeted delivery, leading to improved therapeutic outcomes in preclinical models. This review explores evidence-based the therapeutic potential of chitosan NPs in the management of knee osteoarthritis, focusing on their role in cartilage regeneration and drug delivery.

Evidence indicates that mechanical loading plays an important role in osteoarthritis (OA) progression, while the specific pathological changes of the synovium under excessive mechanical loading are unclear. Results showed that excessive mechanical loading caused pro-inflammation of synovial macrophages, which has been confirmed to exist in OA. High Rapgef3 expression level was found in RNA sequencing of RAW246.7 subjected to 0.5 Hz and 20% cyclic tensile strain. We verified this in the synovium of patients with OA and destabilization of the medial meniscus (DMM)-OA mice. Interestingly, the Rapgef3 content of chondrocytes was very low. Primary chondrocytes treated with Rapgef3 alone did not show metabolic phenotype, but an OA phenotype appeared when treated with Rapgef3-stimulated macrophage culture supernatant. Mechanically, excessive mechanical loading activated p65-nuclear factor κB (NF-κB) pathway through Rapgef3, which promoted the inflammation of macrophage, resulting in severe articular cartilage injury. Intra-articular Rapgef3 knockout reversed synovitis and cartilage degeneration, which might provide a therapeutic target for OA.

Inflammation plays a key role in cartilage damage that occurs in osteoarthritis (OA). However, in vitro assessments of tissue-engineered constructs for cartilage regeneration generally do not consider their performance in the presence of inflammation. In this work, the chondrogenic differentiation potential of mesenchymal stromal cells (MSCs) was evaluated in the presence of both chondrogenic factors and inflammatory cytokines, and cartilage formation, degradative response, and inflammatory response were characterized. The addition of cytokines reduced cartilage production, increased cell proliferation, and resulted in an increase in inflammatory markers. Incorporation of hyaluronic acid (HA) had little impact on both collagen fibril microstructure and mechanical properties, two gel properties known to affect cell response, and thus allows the work to probe the biological impact of HA without the confounding effect of these gel properties. Regardless of in vitro environment, HA did not change cartilage production. The inflammatory response was similar with or without HA in terms of IL-6 and IL-10 secretion whereas IL-8 production exhibited some correlation with HA concentration as observed via a linear regression model. Additionally, in the presence of cytokines, inclusion of HA statistically decreased the gene- and protein-level expression of matrix metalloproteinase-13 (MMP-13). Thus, when exposed to both chondrogenic growth factors and inflammatory cytokines within a chondrogenic-promoting collagen I/II blended hydrogel, chondrogenic differentiation of MSCs was limited by the inflammatory environment. These findings emphasize the importance of understanding how biomaterials affect cell responses within disease-relevant inflammatory environments.

To compare the prevalence and examine the likelihood of insomnia symptoms in middle- and older-aged adults with an osteoarthritis (OA) diagnosis and with joint symptoms indicative of OA but without a diagnosis, in a population-based sample.

Data are from the Canadian Longitudinal Study on Aging (participants aged >45). Individuals reported on doctor-diagnosed OA (hand, hip, or knee) and joint symptoms typical of OA, irrespective of OA diagnosis. A three-level 'OA-status' variable was derived: diagnosed OA; joint symptoms-no OA; no symptoms-no OA (controls). Participants responded to sleep-related questions and were categorized as experiencing insomnia symptoms (yes/no). Logistic regression analysis examined the association between insomnia symptoms and OA status, adjusting for a number of covariates.

Of 21,422 respondents, OA was reported by 29.1% (mean age 68.2) and 17.2% reported joint symptoms-no OA (mean age 63.9). One third of those with diagnosed OA and with joint symptoms-no OA reported insomnia symptoms compared to a quarter of controls. Those with OA and with joint symptoms-no OA were similarly more likely to report insomnia symptoms than controls (odds ratio (OR) 1.25, 95% CI 1.17-1.35 and OR 1.32, 95% CI 1.21-1.43). Also significantly associated with insomnia symptoms were female sex, current smoker, lower activity level, multiple chronic conditions and depressive symptoms. Odds ratio magnitudes were greatest for depressive symptoms (OR 2.50, 95% CI 2.26-2.76), comorbidity count (3 + vs. 0 OR 1.68, 95% CI 1.47-1.91) and female sex (OR 1.46, 95% 1.37-1.55).

Insomnia symptoms were not uncommon among comparatively younger individuals with typical OA joint symptoms and those with OA. This suggests that healthcare providers should address sleep-related issues in those consulting for joint pain, irrespective of diagnosis. Given their high prevalence, this also has implications for sleep-related issues at a population level.

Hand osteoarthritis (OA) is a prevalent and disabling condition, yet its pathogenesis remains less studied than OA in large weight-bearing joints. Emerging genetic, epigenetic, and microbiome research suggests that hand OA might be biologically distinct, involving joint-specific pathways not shared by knee or hip OA. This review integrates genome-wide association studies specific to hand OA, highlighting key molecular contributors such as inflammatory cytokines. These genetic insights, together with emerging data on epigenetic alterations and gut microbial dysbiosis, point to broader systemic and regulatory influences on hand OA onset and progression. We also assess pharmacologic interventions tested in randomized controlled trials that have attempted to target these pathways. While agents such as TNF and IL-6 inhibitors, hydroxychloroquine, and corticosteroids have shown limited success, emerging evidence supports the potential of methotrexate in synovitis-positive general hand OA, platelet-rich plasma in thumb carpometacarpal (CMC) OA, and prolotherapy in interphalangeal (IP) OA. These findings illustrate the persistent gap between mechanistic understanding and therapeutic success. Future work must prioritize multifactorial strategies for addressing pain and translational frameworks that link molecular mechanisms to treatment response. In summary, this review offers an update on hand OA and identifies key opportunities for more targeted and effective therapy.

Notch signaling plays a fundamental role in the inflammatory response and has been linked to the pathogenesis of osteoarthritis in murine models of the disease and in humans. To address how Notch signaling modifies transcriptomes and cell populations, we examined the effects of NOTCH2 in chondrocytes from mice harboring a NOTCH2 gain-of-function mutation (Notch2tm1.1Ecan) and a conditional NOTCH2 gain-of-function model expressing the NOTCH2 intracellular domain (NICD2) from the Rosa26 locus (R26-NICD2 mice). Bulk RNA-Sequencing (RNA-Seq) of primary epiphyseal cells from both gain-of-function models established increased expression of pathways associated with the phagosome, genes linked to osteoclast activity in rheumatoid arthritis signaling and pulmonary fibrosis signaling. Expression of genes linked to collagen degradation was enhanced in Notch2tm1.1Ecan cells, while genes related to osteoarthritis pathways were increased in NICD2-expressing cells. Single cell (sc)RNA-Seq of cultured Notch2tm1.1Ecan cells revealed clusters of cells related to limb mesenchyme, chondrogenic cells and fibroblasts including articular synovial fibroblasts. Pseudotime trajectory revealed close associations among clusters in control cultures, but the cluster of articular/synovial fibroblasts was disrupted in cells from Notch2tm1.1Ecan mice. ScRNA-Seq showed similarities in the cluster distributions and pseudotime trajectories of NICD2-expressing and control cells, except for altered progression in a cluster of NICD2-expressing cells. In conclusion, NOTCH2 enhances the activity of pathways associated with inflammation in epiphyseal chondrocytes and disrupts the transcriptome profile of articular/synovial fibroblasts.

Elucidating the molecular mechanisms underlying orthopedic diseases is crucial for guiding therapeutic strategies and developing innovative interventions. N6-methyladenosine (m6A)-an epitranscriptomic modification-has emerged as a key regulator of cellular fate and tissue homeostasis. Specifically, m6A plays a pivotal role in several RNA biological processes such as precursor RNA splicing, 3'-end processing, nuclear export, translation, and stability. Recent advancements indicate that m6A methylation regulates stem cell proliferation and osteogenic differentiation by modulating various signaling pathways. Extensive research has shown that abnormalities in m6A methylation contribute significantly to the onset and progression of various orthopedic diseases such as osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), and bone tumors. This review aims to summarize the key proteases involved in m6A methylation and their functions. The detailed mechanisms by which m6A methylation regulates osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) through direct and indirect ways are also discussed, with a focus on specific molecular pathways. Finally, this review analyzes the roles and mechanisms of m6A modification in the development and progression of multiple orthopedic diseases, offering a comprehensive understanding of the pathophysiology of these conditions and proposing new directions and molecular targets for innovative treatment strategies.

Inflammation plays a significant role in the pathogenesis of knee post-traumatic osteoarthritis (PTOA) characterized by damage to cartilage and surrounding tissues that results in loss of physiological function. This inflammation is mainly regulated by NF-κB pathway. The TPCA-1 can inhibit IκB kinase (IKK) β in NF-κB pathway. Here, we optimized the delivery of TPCA-1 to the damaged knee joint via targeted nanosomes and examined its effects in a mouse model of PTOA. PTOA was induced in mice through a modified cyclic mechanical loading method. Mice were divided into groups receiving vehicle, TPCA-1 solution, or TPCA-1-loaded nanosomes. A concentration of 100 μM TPCA-1 was used based on preliminary studies. Control groups included untreated and vehicle-treated animals. Treatment efficacy was assessed using in vivo imaging, serum biochemical assays, gene expression analysis of cartilage tissues, histopathology, and behavioral analysis. Mechanical loading induced significant knee joint damage in the model. TPCA-1 nanosomes notably attenuated the adverse effects of loading, outperforming both the vehicle and TPCA-1-solution in reducing inflammation. Notably, serum levels of total NO and LDH were significantly lower in the TPCA-1-nanosome group. Inflammation, as indicated by MMP13 and IL1β gene expression, was substantially reduced. Enhanced cartilage preservation and function were confirmed through IVIS imaging, histological assessments, and improved behavior metrics. The targeted delivery of TPCA-1 via nanosomes effectively inhibits the NF-κB pathway, leading to significant reductions in inflammation and cartilage damage in a PTOA mouse model. This strategy demonstrates potential as a therapeutic intervention for managing inflammation and preserving joint health in osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, inflammation, and pain. Recent studies highlight the gut-joint axis, suggesting that gut microbiota influences joint health by modulating systemic inflammation and immune responses. This study investigated the effects of Latilactobacillus sakei LB-P12 on cartilage degradation and joint inflammation in a monosodium iodoacetate induced rat model of OA. OA severity was assessed through histological analysis, weight-bearing and micro-computed tomography (Micro-CT). Serum Interleukin 6 (IL-6) and prostaglandin E2 (PGE2) levels, along with interleukin-1β (Il1b) and matrix metalloproteinase 13 (Mmp13) expression in knee tissue, were measured. Then, the effect of L. sakei LB-P12 on inflammatory responses in interleukin-1β pretreated chondrocytes has also been investigated. The L. sakei LB-P12 improved weight-bearing distribution and reduced cartilage damage based on histological scores. Micro-CT showed increased bone volume fraction and bone mineral density. Treatment reduced serum IL-6 and PGE2 levels and suppressed Il1b and Mmp13 expression in knee tissues. In vitro, L. sakei LB-P12 inhibited lipopolysaccharide induced pro-inflammatory cytokines and nitric oxide production in macrophages. It also downregulated the expression of Epas1, which encodes hypoxia-inducible factor-2α (HIF-2α), and Mmp13 in IL-1β stimulated chondrocytes. L. sakei LB-P12 shows potential as a dietary supplement for alleviating OA-related pain, cartilage degradation, and inflammation by suppressing the nuclear factor-κB (NF-κB)/ HIF-2α pathway.

Osteoarthritis (OA) is a low-grade inflammatory disease that is highly associated with severe hyperplasia of the synovial membrane and the degeneration of cartilage. Interleukin-10 (IL-10), has been extensively studied, while its receptor, IL-10Rα, has not been widely mentioned in the context of OA. A significant difference is found in the expression of IL-10Rα in synovial macrophages from normal and OA patients, along with a marked increase in the glycolytic activity of synovial macrophages. In IL-10RαLysm OA mice, the specific deficiency of IL-10Rα exacerbated the progression of OA. Mechanistically, hypoxia-inducible factor-1α (HIF-1α) is identified as a key transcription factor, and its inhibition significantly weakened the glycolytic process. Additionally, differences in ferroptosis of chondrocytes are observed. After co-culturing the two types of cells in vitro, a significant connection is found between the glycolytic state of synovial macrophages and the ferroptosis of chondrocytes. To achieve targeted therapy, MI@UN, a biomimetic nanoparticle encapsulating NO-prednisolone in UIO-66-NH2, surface-modified with IL-10, and coated with macrophage membranes (MM), is developed. It significantly slows osteoarthritis progression in mice. This offers new insights into OA pathogenesis, highlighting IL-10Rα as a therapeutic target and supporting MI@UN's translational use for OA treatment.

Paraptosis is a novel form of programmed cell death, generally caused by disrupted proteostasis or alterations of redox homeostasis. However, its impact and underlying mechanisms on the pathology of osteoarthritis (OA) are still unclear. This study aimed to investigate the role and regulatory mechanism of SHP2 in chondrocyte paraptosis and the effects influenced by low-intensity pulsed ultrasound (LIPUS).

SHP2, a MAPK upstream intermediary, has been identified as one of the critical targets of IL-1β-induced paraptosis in the GEO and GeneCard databases. The expression of SHP2 in chondrocytes was regulated by either siRNA knockdown or plasmid overexpression. Additionally, adeno-associated viruses were injected into the knee joints of rats to explore whether SHP2 plays a role in the development of OA. The impact of LIPUS on paraptosis and OA was examined in IL-1β-induced chondrocytes and a post-traumatic OA model, with SHP2 regulation assessed at both cellular and animal levels.

An increase in cellular reactive oxygen species (ROS) caused by IL-1β halts the growth of chondrocytes and induces paraptosis in the chondrocytes. IL-1β-induced paraptosis, manifested as endoplasmic reticulum (ER)-derived vacuolization, was mediated by ROS-mediated ER stress and MAPK activation. SHP2 facilitates ROS production, thereby exacerbating the chondrocytes paraptosis. SHP2 knockdown and ROS inhibition effectively reduced this process and significantly mitigated inflammation and cartilage degeneration. Furthermore, we discovered that LIPUS delayed OA progression by inhibiting the activation of the MAPK pathway, ER stress, and ER-derived vacuoles in chondrocytes, all of which play critical roles in paraptosis, through the downregulation of SHP2 expression. Results on animals showed that LIPUS inhibited cartilage degeneration and alleviated OA progression.

SHP2 exacerbates IL-1β-induced oxidative stress and the subsequent paraptosis in chondrocytes, promoting OA progression. LIPUS mitigates paraptosis by modulating SHP2, which in turn slows OA progression.

This study indicates that a novel SHP2-mediated cell death mechanism, paraptosis, plays a role in post-traumatic OA progression. LIPUS helps maintain cartilage-subchondral bone unit integrity by targeting SHP2 inhibition. SHP2 emerges as a potential therapeutic target, while LIPUS provides a promising non-invasive approach for treating trauma-related OA.

Osteoarthritis (OA) is a multifactorial degenerative disorder entailing cartilage loss and progressive joint failure. m6A RNA methylation could impact multiple disorders, including OA. In this study, m6A methylation regulator WTAP was down-regulated in OA cartilage, accompanied by significantly lower m6A methylation levels in OA tissues. In the DMM-induced mice OA model and IL-1β- or TNF-α-stimulated chondrocytes, WTAP and m6A methylation levels were decreased, but IL-1β, IL-6, and TNF-α cytokine expressions were elevated. In vivo and in vitro, WTAP overexpression increased m6A methylation levels but reduced proinflammatory cytokine contents. Furthermore, WTAP overexpression (OE) increased chondrocyte viability and proliferation, aggrecan and collagen II protein, and decreased cell apoptosis, MMP3, MMP13, and ADAMTS5. WTAP-mediated m6A methylation of IL-33 and impaired IL-33 mRNA stability. IL-33 OE caused no changes to WTAP expression; however, IL-33 OE partially attenuated WTAP OE-induced IL-33 downregulation. IL-33 overexpression inhibited chondrocyte viability and proliferation, decreased aggrecan and collagen II but elevated MMP3, MMP13, and ADAMTS5, and increased cell apoptosis and proinflammatory cytokine contents. More importantly, IL-33 eliminated the effects of WTAP OE on chondrocytes. Therefore, WTAP is down-regulated in OA; WTAP improves chondrocyte proliferation and function, thereby ameliorating OA through mediating m6A methylation of IL-33 and impairing IL-33 mRNA stability.

Matrix metalloproteinases (MMPs), coupled with other proteinases and glycanases, can degrade proteoglycans, collagens, and other extracellular matrix (ECM) components in inflammatory and non-inflammatory arthritis, making them important pathogenic molecules and ideal disease indicators and pharmaceutical intervention triggers. For MMP responsiveness, MMP-sensitive peptides (MSPs) are among the most easily synthesized and cost-effective substrates, with free terminal amine and/or carboxyl groups extensively employed in multiple designs. We hereby provide a comprehensive review over the mechanisms and advances in MSP applications for the management of arthritis. These applications include early and precise diagnosis of MMP activity via fluorescence probe technologies; acting as nanodrug carriers to enable on-demand drug release triggered by pathological microenvironments; and facilitating cartilage engineering through MMP-mediated degradation, which promotes cell migration, matrix synthesis, and tissue integration. Specifically, the ultra-sensitive MSP diagnostic probes could significantly advance the early diagnosis and detection of osteoarthritis (OA), while MSP-based drug carriers for rheumatoid arthritis (RA) can intelligently release anti-inflammatory drugs effectively during flare-ups, or even before symptoms manifest. The continuous progress in MSP development may acceleratedly lead to novel management regimens for arthropathy in the future.

Abnormal mechanical stress is a key factor in osteoarthritis (OA) pathogenesis. This study aims to investigate the role of the mechanosensitive ion channel Piezo1 in activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and its contribution to cartilage degradation in OA.

We conducted both in vivo and in vitro experiments. In vitro, chondrocytes were subjected to mechanical stress, and Piezo1 expression, calcium ion (Ca2+) influx, and mitochondrial permeability changes were analyzed. In vivo, Piezo1 conditional knockout (Col2a1CreERT; Piezo1flox/flox) mice were used to assess the activation of the cGAS-STING pathway and cartilage degradation. Additionally, the effects of STING inhibitors on inflammation and OA progression were evaluated.

Mechanical stress significantly increased Piezo1 expression and Ca2+ influx in chondrocytes, leading to mitochondrial Ca2+ overload and mitochondrial DNA (mtDNA) release. This triggered activation of the cGAS-STING pathway (9.35[95%Confidence Interval (CI) 1.378 to 18.032], n=3 biologically independent samples), resulting in inflammatory responses (4.185[95%CI 0.411 to 8.168], n=3 biologically independent samples). In Piezo1 knockout mice, cGAS-STING activation (-7.23[95%CI -10.52 to -3.89], n=6) and cartilage degradation (Osteoarthritis Research Society International (OARSI) grade; -3.651[95%CI -5.562 to -1.681] n=6) were reduced. STING inhibitors effectively decreased inflammation (-8.95[95%CI -17.24 to -1.31], n=3 biologically independent samples) and slowed OA progression (OARSI grade; -2.76 [95%CI -4.37 to -1.08], n=6) in both in vivo and in vitro models.

Mechanical stress induces mtDNA release via Piezo1 activation, which triggers the cGAS-STING pathway and exacerbates cartilage degradation. Targeting Piezo1 or the cGAS-STING pathway may offer a promising therapeutic strategy to reduce inflammation and protect cartilage in OA.

Osteoarthritis (OA), a prevalent joint disorder, can lead to disability, with no effective treatment available. Interleukin-1 (IL-1) plays a crucial role in the progression of OA, and its receptor antagonist (IL-1Ra), a natural IL-1 inhibitor, represents a promising therapeutic target by obstructing the IL-1 signaling pathway. This study delivered IL-1Ra via adeno-associated virus (AAV), a gene therapy vector enabling long-term protein expression, to treat knee osteoarthritis (KOA) in animal models. scAAV-oIL-1Ra-I1/2 injected directly into the joint in both MMT/ACLT-induced KOA model rat improved abnormal gait (increasing footprint area and pressure), subchondral bone lesions, and significantly reduced cartilage wear and pathological scores. In the MMT-induced KOA rabbit model, weight-bearing asymmetry (indicating pain) improved after 8 weeks of scAAV-oIL-1Ra-I1/2 administration, and X-ray showed decreased K-L scores (severity grade), reduced cartilage loss, and lower pathology scores compared to untreated animals. Additionally, sex-determining region Y-type high mobility group box 9 (SOX9) was co-delivered with IL-1Ra via AAV in ACLT + MMT-induced KOA rats. The combined treatment significantly alleviated subchondral bone lesions, cartilage destruction, synovial inflammation, and pathological scores, demonstrating superior efficacy compared to either treatment administered alone. Co-delivering IL-1Ra and SOX9 inhibited IL-1 mediated inflammatory signaling, maintained cartilage homeostasis, and promoted its repair in KOA models, suggesting potential for clinical use.

Osteoarthritis (OA), a degenerative disease characterized by cartilage degradation and inflammation, occurs due to trauma caused by external stimuli or cartilage aging. Pyropia yezoensis is a red alga that belongs to the Porphyra family and is consumed as food in Asia, especially Korea, Japan, and China. P. yezoensis contains various bioactive substances, including carotenoids, flavonoids, and vitamins, that exert anti-inflammatory, antioxidant, and anti-photoaging effects. In the present study, the anti-osteoarthritic effects of 30% fermented alcohol extract of P. yezoensis (30% FEPY) on interleukin-1 beta (IL-1β)-stimulated chondrocytes and a destabilization of the medial meniscus (DMM)-induced OA rat model were investigated. The results showed that pretreatment with 30% FEPY significantly reduced the IL-1β-induced expression of inflammatory factors (e.g., inducible nitric oxide synthase and cyclooxygenase-2) and cartilage-degrading enzymes [matrix metalloproteinase (MMP) 1, MMP3, MMP13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4, and ADAMTS5], which was analyzed using Griess reaction, enzyme-linked immunosorbent assay, and Western blot analysis. The anti-osteoarthritic effects of 30% FEPY, which were mediated through mitogen-activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cell signaling, were analyzed using Western blot analysis. In an in vivo study, Safranin O staining and immunohistochemistry analysis revealed that treatment with 30% FEPY significantly increased cartilage degradation and collagen type II protein expression in the DMM group. These findings collectively suggest that 30% FEPY is a promising candidate for alleviating OA progression and developing new therapeutic drugs.

Osteoarthritis (OA) is a common degenerative joint disease that can lead to chronic pain and disability. The pathogenesis of OA involves chronic low-grade inflammation, characterized by the degradation of chondrocytes, inflammation of the synovium, and systemic low-grade inflammation. This inflammatory response accelerates the progression of OA and contributes to pain and functional impairment. Primary cilia play a crucial role in cellular signal transduction and the maintenance of cartilage matrix homeostasis, and their dysfunction is closely linked to inflammatory responses. Given these roles, primary cilia may significantly contribute to the pathogenesis of OA. This review explores inflammation-associated signaling pathways in OA, including NF-κB, MAPK, JAK/STAT, and PI3K/AKT/mTOR signaling. In addition, we place particular emphasis on cilia-mediated inflammatory modulation in OA. Primary cilia mediate chondrocyte responses to mechanical loading and inflammatory cytokines via pathways including NF-κB, MAPK, TRPV4, and Hedgehog signaling. Notably, alterations in the length and incidence of primary cilia in chondrocytes during OA further underscore their potential role in disease pathogenesis. The identification of biomarkers and therapeutic targets related to primary cilia and inflammatory pathways offers new potential for the treatment and management of OA.

Bone is the main structure of the human body; it mainly plays a supporting role and participates in metabolic processes. The Hippo signaling pathway is composed of a series of protein kinases, including the mammalian STE20-like kinase MST1/2 and the large tumor suppressor LATS1/2, which are widely involved in pathophysiological processes, including cell proliferation, differentiation, apoptosis and death, especially those related to biomechanical transduction in vivo. However, the role of it in regulating skeletal system development and the evolution of bone-related diseases remains poorly understood. The pathway can intervene in and regulate the physiological activities of bone-related cells such as osteoclasts and chondrocytes through its own or other bone-related signaling pathways, such as the Wnt pathway, the Notch pathway, and receptor activator of nuclear factor-κB ligand (RANKL), thereby affecting the occurrence and development of bone diseases. This article discusses the role of the Hippo signaling pathway in bone development and disease to provide new insights into the treatment of bone-related diseases by targeting the Hippo signaling pathway.

In the current perspective and review article, we address the human body as a living ecosystem with collecting watersheds and draining hydrosheds; we integrate our discoveries over the past quarter of a century and pose the critical open research questions to be addressed going forward, with the aim to improve cell, tissue, organ and organismal health. First, we address the flow of fluid through the tissues of the musculoskeletal system, after which we describe the interactions of the fluid, at multiple lengths and time scales, with the molecular to macroscopic non-fluid tissue components, discussing bone and tissues in the context of "living" chromatography and/or electrophoresis columns. Thereafter, we discuss the implications of functional barrier integrity, and the effects of cytokines on active barrier function and molecular transport between organ systems, tissue compartments, and within tissues. In addition, we address the fluid and its flow and the multi-physics implications thereof for the living inhabitants of tissues, i.e., the cells. Finally, we describe the implications of the solid and fluid components and the cellular inhabitants on ecosystem health, where the tissues and organs comprise the organism form interacting ecosystems throughout life and in the context of health and disease. By taking convergent approaches to understanding musculoskeletal, human and environmental health (which themselves are interdependent), we hope to pave new paths of innovation and discovery, to improve the lives of our worlds' inhabitants, from the worlds of our bone and joints and bodies to the interacting ecosystems of our Earth to unknown worlds beyond our current understanding.

Chronic inflammation (an abnormal state) and autoimmune disease (AD) can both cause multiple organ damage. AD is a heterogeneous group of diseases due to immune dysfunction. Chronic inflammation is closely related to AD and is an important part of AD. With the increasing prevalence of AD, researchers are constantly exploring new drugs with small side effects, considerable curative effects, and lower costs. Kaempferol, a flavonoid, possesses a range of biological functions, including antioxidant, anti-inflammatory, anti-neoplastic, and immunomodulatory capabilities. This compound is prevalent in a variety of plant sources, such as vegetables, fruits, and medicinal herbs traditionally used in Chinese medicine. A plethora of empirical evidence from animal-based research supports the assertion that this particular substance exhibits both anti-inflammatory and immunomodulatory effects, with the curative effect being significant and application prospects. This article mainly summarizes and discusses the pharmacokinetics, drug delivery system, and the mechanism of kaempferol on immune cells, cytokines, signaling pathways, and other aspects. This paper summarizes the existing kaempferol drug delivery system, analyzes the possibility and limitations of kaempferol as a new anti-inflammatory and immunomodulatory drug, and discusses how to apply it in clinical practice. Therefore, kaempferol can more effectively exert its anti-inflammatory and immune-modulating effects, thereby demonstrating therapeutic potential in clinical settings, while reducing patient burden.

Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome is a rare autoinflammatory disease characterized by cutaneous manifestations and osteoarticular damage. The pathogenesis of SAPHO syndrome has not yet been elucidated, but studies have shown that the abnormal bone metabolism of patients with SAPHO syndrome is most likely due to localized infections that induce immune disorders in the body. Although no standardized treatment protocols exist, based on existing case studies and data from open studies, we propose that the treatment of SAPHO syndrome can be categorized into three areas according to the symptomatic manifestations of the disease: (1) control of focal infections using antibiotics and tonsillectomy; (2) administration of DMARDs to manage disease progression; and (3) bone remodeling therapy with bisphosphonates to address abnormal bone metabolism. Furthermore, a comprehensive treatment approach tailored to the clinical manifestations of the patient can effectively alleviate symptoms and enhance quality of life.

Osteoarthritis (OA) is a multifactorial disease in which low-grade inflammation is considered to play a pivotal role. Although colchicine is a widely used anti-inflammatory drug in the treatment of gout, its effect in OA is still disputed due to inconsistent results of short-term clinical trials. Therefore, we aim to evaluate the effect of long-term colchicine 0.5 mg once daily on the incidence of knee or hip replacements in patients with knee or hip OA.

The ECHO trial is a prospective, multicentre, randomised, double-blind, placebo-controlled, phase III trial in which 1200 participants with knee or hip OA tolerant to colchicine during a 30-day run-in period will be 1:1 randomised to colchicine 0.5 mg once daily or matching placebo using concealed allocation. The primary endpoint is the time from randomisation to the first knee or hip replacement assessed up to 4.5 years. Secondary endpoints include course of pain, physical function, joint space narrowing, low-grade inflammation, quality of life, clinical or radiological onset of OA in a new joint group other than present at baseline, number of participants using pain medication during the study, onset of new cardiovascular events (ie, myocardial infarction, ischaemia-driven coronary revascularisation, ischaemic stroke, peripheral artery disease or cardiovascular death) and direct and indirect costs related to treatment and disease burden due to OA. Harm-related endpoints include the number of (serious) adverse events, the number of withdrawals due to (serious) adverse events and changes in laboratory data (ie, serum creatinine, estimated glomerular filtration rate and alanine transferase) throughout the study. The primary analysis will be performed according to the intention-to-treat principle.

This trial has been approved by the Medical Ethics Review Committee East-Netherlands. Findings will be presented at scientific meetings and published in a peer-reviewed scientific journal.

NCT06578182.