Early-stage Osteoarthritis Research Articles

Understanding the role of machine learning in predicting progression of osteoarthritis.

Machine learning (ML), a branch of artificial intelligence that uses algorithms to learn from data and make predictions, offers a pathway towards more personalized and tailored surgical treatments. This approach is particularly relevant to prevalent joint diseases such as osteoarthritis (OA). In contrast to end-stage disease, where joint arthroplasty provides excellent results, early stages of OA currently lack effective therapies to halt or reverse progression. Accurate prediction of OA progression is crucial if timely interventions are to be developed, to enhance patient care and optimize the design of clinical trials. A systematic review was conducted in accordance with PRISMA guidelines. We searched MEDLINE and Embase on 5 May 2024 for studies utilizing ML to predict OA progression. Titles and abstracts were independently screened, followed by full-text reviews for studies that met the eligibility criteria. Key information was extracted and synthesized for analysis, including types of data (such as clinical, radiological, or biochemical), definitions of OA progression, ML algorithms, validation methods, and outcome measures. Out of 1,160 studies initially identified, 39 were included. Most studies (85%) were published between 2020 and 2024, with 82% using publicly available datasets, primarily the Osteoarthritis Initiative. ML methods were predominantly supervised, with significant variability in the definitions of OA progression: most studies focused on structural changes (59%), while fewer addressed pain progression or both. Deep learning was used in 44% of studies, while automated ML was used in 5%. There was a lack of standardization in evaluation metrics and limited external validation. Interpretability was explored in 54% of studies, primarily using SHapley Additive exPlanations. Our systematic review demonstrates the feasibility of ML models in predicting OA progression, but also uncovers critical limitations that currently restrict their clinical applicability. Future priorities should include diversifying data sources, standardizing outcome measures, enforcing rigorous validation, and integrating more sophisticated algorithms. This paradigm shift from predictive modelling to actionable clinical tools has the potential to transform patient care and disease management in orthopaedic practice.

Maximizing Knee OA Treatment: A Comparative Look at Physiotherapy and Injections

Background: Knee osteoarthritis (OA) is a prevalent and disabling condition often managed with physiotherapy or intra-articular injections. However, the comparative effectiveness of these treatments remains unclear. This systematic review aimed to evaluate and compare the efficacy of physiotherapy and intra-articular injections in managing knee OA. Methods: A systematic search of PubMed, Scopus, Web of Science, PEDro, and Cochrane Library was conducted. Randomized controlled trials (RCTs) comparing physiotherapy and intra-articular injections in knee OA patients were included. Key outcomes included pain (VAS), function (WOMAC, KOOS), range of motion (ROM), and quality of life. Data from five studies with a total of 552 participants were analyzed. Results: Intra-articular injections, particularly botulinum toxin and hyaluronic acid, were found to provide rapid pain relief, outperforming physiotherapy in short-term pain management. However, physiotherapy contributed significantly to long-term functional improvements, particularly in early-stage OA. Combination therapy of injections and physiotherapy yielded the best short-term pain relief and functional outcomes. Heterogeneity in study designs and follow-up periods limited the generalizability of findings. Conclusions: Intra-articular injections are effective for immediate pain control, while physiotherapy plays a crucial role in maintaining joint function, especially for long-term management. Combining both interventions may offer the most comprehensive benefits. Further research is needed to determine the long-term efficacy of these treatments.

Chondrocyte autophagy mechanism and therapeutic prospects in osteoarthritis.

Osteoarthritis (OA) is the most common type of arthritis characterized by progressive cartilage degradation, with its pathogenesis closely related to chondrocyte autophagy. Chondrocytes are the only cells in articular cartilage, and the function of chondrocytes plays a vital role in maintaining articular cartilage homeostasis. Autophagy, an intracellular degradation system that regulates energy metabolism in cells, plays an incredibly important role in OA. During the early stages of OA, autophagy is enhanced in chondrocytes, acting as an adaptive mechanism to protect them from various environmental changes. However, with the progress of OA, chondrocyte autophagy gradually decreases, leading to the accumulation of damaged organelles and macromolecules within the cell, prompting chondrocyte apoptosis. Numerous studies have shown that cartilage degradation is influenced by the senescence and apoptosis of chondrocytes, which are associated with reduced autophagy. The relationship between autophagy, senescence, and apoptosis is complex. While autophagy is generally believed to inhibit cellular senescence and apoptosis to promote cell survival, recent studies have shown that some proteins are degraded by selective autophagy, leading to the secretion of the senescence-associated secretory phenotype (SASP) or increased SA-β-Gal activity in senescent cells within the damaged region of human OA cartilage. Autophagy activation may lead to different outcomes depending on the timing, duration, or type of its activation. Thus, our study explored the complex relationship between chondrocyte autophagy and OA, as well as the related regulatory molecules and signaling pathways, providing new insights for the future development of safe and effective drugs targeting chondrocyte autophagy to improve OA.

ESC-sEVs alleviate non-early-stage osteoarthritis progression by rejuvenating senescent chondrocytes via FOXO1A-autophagy axis but not inducing apoptosis

Osteoarthritis (OA) is a common joint degenerative disease which currently lacks satisfactory disease-modifying treatments. Oxidative stress-mediated senescent chondrocytes accumulation is closely associated with OA progression, which abrogates cartilage metabolism homeostasis by secreting senescence-associated secretory phenotype (SASP) factors. Numerous studies suggested mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have been regarded as promising candidates for OA therapy. However, MSC-sEVs were applied before the occurrence of cartilage degeneration or at early-stage OA, while in clinical practice, most OA patients who present with pain are already in non-early-stage. Recently, embryonic stem cells-derived sEVs (ESC-sEVs) have been reported to possess powerful anti-aging effects. However, whether ESC-sEVs could attenuate non-early-stage OA progression remains unknown. In this study, we demonstrated ESC-sEVs ameliorated senescent phenotype and cartilage destruction in both mechanical stress-induced non-early-stage posttraumatic OA and naturally aged mice. More importantly, we found ESC-sEVs alleviated senescent phenotype by rejuvenating aged chondrocytes but not inducing apoptosis. We also provided evidence that the FOXO1A-autophagy axis played an important role in the anti-aging effects of ESC-sEVs. To promote clinical translation, we confirmed ESC-sEVs reversed senescent phenotype in ex-vivo cultured human end-stage OA cartilage explants. Collectively, our findings reveal that ESC-sEVs-based therapy is of high translational value in non-early-stage OA treatment.

PP2Ac Regulates Autophagy via Mediating mTORC1 and ULK1 During Osteoclastogenesis in the Subchondral Bone of Osteoarthritis.

The molecular mechanism underlying abnormal osteoclastogenesis triggering subchondral bone remodeling in osteoarthritis (OA) is still unclear. Here, single-cell and bulk transcriptomics sequencing analyses are performed on GEO datasets to identify key molecules and validate them using knee joint tissues from OA patients and rat OA models. It is found that the catalytic subunit of protein phosphatase 2A (PP2Ac) is highly expressed during osteoclastogenesis in the early stage of OA and is correlated with autophagy. Knockdown or inhibition of PP2Ac weakened autophagy during osteoclastogenesis. Furthermore, the ULK1 expression of the downstream genes is significantly increased when PP2Ac is knocked down. PP2Ac-mediated autophagy is dependent on ULK1 phosphorylation activity during osteoclastogenesis, which is associated with enhanced dephosphorylation of ULK1 Ser637 residue regulating at the post-translational level. Additionally, mTORC1 inhibition facilitated the expression level of PP2Ac during osteoclastogenesis. In animal OA models, decreasing the expression of PP2Ac ameliorated early OA progression. The findings suggest that PP2Ac is also a promising therapeutic target in early OA.

Postoperative Radiographic Outcomes Following Abduction-Extension Metacarpal Osteotomy: A Comparison between Early and Advanced Carpometacarpal Arthritis.

Background: This study aimed to investigate the effect of thumb metacarpal osteotomy on dorsal subluxation of the carpometacarpal (CMC) joint and compare the effects of early and advanced osteoarthritis (OA). Methods: We retrospectively reviewed 42 thumbs of 37 patients who underwent metacarpal osteotomy with a postoperative extension angle of 90° or more between January 2018 and October 2021 and were followed up for more than 2 years. The thumbs were classified into two groups: early OA (Eaton stage I or II) and advanced OA (Eaton stage III). We measured the reduction ratio, which was defined as the ratio of improvement in dorsal subluxation, at 3 months and 1 year postoperatively, and at the latest follow-up. We statistically compared the reduction ratio between the two groups and investigated the factors affecting the reduction ratio using correlation analysis. Results: The reduction ratio was significantly higher in the early OA group than in the advanced OA group at 3 months after surgery, whereas no significant difference was found between the two groups at 1 year after surgery and at the latest follow-up. A significant positive correlation was detected between the reduction ratio and the postoperative extension angle. Conclusions: First metacarpal osteotomy reduces dorsal subluxation in both early- and advanced-stage CMC OA. This procedure yields immediate marked reduction in early-stage OA, while improvement of the subluxation progressed gradually in advanced-stage OA. Level of Evidence: Level IV (Therapeutic).

A multi-modal evaluation of experimental pain and psychological function in women with carpometacarpal osteoarthritis

ObjectiveThumb carpometacarpal osteoarthritis (CMC1 OA) is a prevalent and debilitating condition that lacks effective treatments. Understanding the multidimensional pain experience across CMC1 OA disease stages is crucial to improving treatment outcomes. This study examined how radiographic CMC1 OA severity is associated with physical, psychological, and somatosensory function. MethodThirty-one women with early-stage (Eaton-Littler 1–2) or end-stage (Eaton-Littler 3–4) radiographic CMC1 OA completed validated questionnaires to assess pain, disability, and psychological function. Additionally, experimental pain was measured in each participant using quantitative sensory testing (QST) (mechanical, pressure, vibratory, thermal) at seven body sites (thenar, hypothenar, brachioradialis bi-laterally; quadriceps on affected side). Cohort differences (early-vs. end-stage) across all variables were analyzed using a multivariable modeling approach that included fixed effects and interactions; notably, age was controlled as a confounder. ResultsEnd-stage CMC1 OA participants had higher scores in the pain (p ​= ​0.01) and function (p ​= ​0.02) portions of the AUSCAN assessment, self-reported disability of the DASH questionnaire (p ​= ​0.04), and painDETECT scores (p ​= ​0.03), indicating greater pain and disability compared to early-stage participants. Additionally, end-stage CMC1 OA participants demonstrated reduced vibratory detection and heat pain thresholds at multiple body sites (p's ​< ​0.05), with significant interactions observed across the mechanical and cold stimuli. ConclusionFindings revealed women with end-stage CMC1 OA exhibited increased neuropathic pain characteristics and somatosensory loss compared to those with early-stage CMC1 OA. These results underscore the importance of addressing both peripheral and centralized pain mechanisms and the need for multimodal approaches in the treatment of CMC1 OA.

A nomoscore of four genes for predicting the rupture risk in abdominal aortic aneurysm patients with osteoarthritis

BackgroundAbdominal aortic aneurysm (AAA) represents one of the most life-threatening cardiovascular diseases and is increasingly becoming a significant global public health concern. The aneurysms-osteoarthritis syndrome (AOS) has gained recognition, as patients with this syndrome often exhibit early-stage osteoarthritis (OA) and have a substantially increased risk of rupture, even with mild dilation of the aneurysm. The aim of this study was to discover potential biomarkers that can predict the occurrence of AAA rupture in patients with OA. MethodsTwo gene expression profile datasets (GSE98278, GSE51588) and two single-cell RNA-seq datasets (GSE164678, GSE152583) were obtained from the GEO database. Functional enrichment analysis, PPI network construction, and machine learning algorithms, including LASSO, Random Forest, and SVM-RFE, were utilized to identify hub genes. In addition, a nomogram and ROC curves were generated to predict the risk of rupture in patients with AAA. Moreover, we analyzed the immune cell infiltration in the AAA tissue microenvironment by CIBERSORT and validated key gene expression in different macrophage subtypes through single-cell analysis. ResultsA total of 105 intersecting DEGs that showed consistent changes between rAAA and OA dataset were identified. From these DEGs, four hub genes (PAK1, FCGR1B, LOX and PDPN) were selected by machine learning. High predictive performance was observed for the nomogram based on these hub genes, with an AUC of 0.975 (95 % CI: 0.942–1.000). Abnormal immune cell infiltration was detected in rAAA and correlated significantly with the hub genes. Ruptured AAA cases exhibited higher nomoscore values and lower M2 macrophage infiltration compared to stable AAA. Validation in animal models (PPE+BAPN-induced rAAA) confirmed the significant role of these biomarkers in AAA pathology. ConclusionThe present study successfully identified four potential hub genes (PAK1, FCGR1B, LOX and PDPN) and developed a robust predictive nomogram to assess the risk of AAA rupture. The findings also shed light on the connection between hub genes and immune cell components in the microenvironment of rAAA. These findings support future research on key genes in AAA patients with OA, providing insights for novel management strategies for AAA.

Precise Lubrication and Protection of Cartilage Damage by Targeting Hydrogel Microsphere.

Osteoarthritis (OA) is a degenerative bone and joint disease characterized by decreased cartilage lubrication, leading to continuous wear and ultimately irreversible damage. This situation is particularly challenging for early-stage OA, as current bio-lubricants lack precise targeting for small inflammatory lesions. In this work, an antibody-mediated targeting hydrogel microspheres (HMS) is developed to precisely lubricate the local injury site of cartilage and prevent the progression of early OA. Anti-Collagen type I (Anti-Col1) is an antibody that targets cartilage injury sites in early OA stages. It is anchored on a HMS matrix made of Gelatin methacrylate (GelMA) and poly (sulfobetaine methacrylate) (PSBMA) to create targeted HMS (T-G/S HMS). The T-G/S HMS's high hydrophilicity, along with the dynamic interaction between its surficial Anti-Col1 and the Col1 on cartilage injury site, ensures its precise and effective lubrication of early OA lesions. Consequently, injecting T-G/S HMS into rats with early OA significantly slows disease progression and reduces symptoms. In conclusion, the developed injectable targeted lubricating HMS and the precisely targeted lubrication strategy represent a promising, convenient technique for treating OA, particularly for slowing the early-stage OA progression.

Kinetics and Retention of Polystyrenesulfonate for Proteoglycan Replacement in Cartilage.

Tissue hydration provides articular cartilage with dynamic viscoelastic properties. Early stage osteoarthritis (OA) is marked by loss of proteoglycans and glycosaminoglycans (GAG), lowering fixed charge density, and impairing tissue osmotic function. The most common GAG replacement, chondroitin sulfate (CS), has failed to show effectiveness. Here, we investigated a synthetic polyelectrolyte, poly(styrenesulfonate) (PSS), both as a model compound to investigate polyelectrolyte transport in cartilage, and as a potential candidate to restore bulk fixed charge density in cartilage with GAG loss. Through bovine explants and histology, we determined zonal-based effective diffusion coefficients for three different molecular weights of PSS. Compared to CS, PSS was retained longer in GAG-depleted cartilage in static and compression-based desorption experiments. We explained enhanced solute performance of PSS by its more compact morphology and higher charge density by small-angle X-ray scattering. This study may improve design of GAG mimetic molecules for repairing osmotic function in OA cartilage.

Increased femoral cartilage thickness in acne patients using isotretinoin: could it be a sign of early osteoarthritis?

Vitamin A derivatives have inhibitory effects on cartilage tissue, such as decreasing chondrocyte proliferation and collagen synthesis, and increasing the loss of glycosaminoglycans and proteoglycans. Therefore, isotretinoin (a vitamin A derivative) may play a role in the pathogenesis of cartilage-related diseases like osteoarthritis by affecting the balance of cartilage tissue. The aim of this study was to evaluate the distal femoral cartilage thickness in acne patients under the systemic isotretinoin therapy and to determine whether it constitutes a risk factor for the development of osteoarthritis. The study included 52 patients (42 female, 10 male, mean age 23.31 ± 3.89 years) who were prescribed systemic isotretinoin for acne and completed at least 3 months of treatment, along with 45 healthy controls ((35 female, 10 male, mean age 23.85 ± 4.77 years). Bilateral distal femoral cartilage thickness was measured by ultrasonography before isotretinoin treatment and after the completion of the third month of treatment. After treatment, a statistically significant increase was found in the thickness of the right medial, right lateral, left medial, left lateral, and left intercondylar cartilage (p = 0.014, 0.012, 0.019, 0.027, 0.002, respectively). There was also an increase in the right intercondylar cartilage thickness, but this was not statistically significant (p = 0.1). Systemic isotretinoin seems to make cartilage thicker. The increase in femoral cartilage thickness observed after short-term isotretinoin treatment might be an indicator of very early-stage osteoarthritis. Extended follow-up studies with larger participant pools are necessary to substantiate this result.

Injectable Regenerated Silk Fibroin Micro/Nanosphere with Enhanced Permeability and Stability for Osteoarthritis Therapy.

In the therapy of early-stage osteoarthritis, to accomplish full infiltration of subchondral bone and cartilage, and to target osteoclast and chondrocyte simultaneously remain challenges in biomaterials design. Herein, a novel hierarchical drug delivery system is introduced, with micrometer-scale outer layer spheres composed of regenerated silk fibroin, characterized by connected porous structure through the n-butanol and regenerated silk fibroin combined emulsion route and freezing method. The design effectively resists clearance from the joint cavity, ensuring stable delivery and prolonged residence time within the joint space. Additionally, the system incorporates phenylboronic acid-enriched silk fibroin nanoparticles, stabilized through chemical cross-linking, which encapsulate isoliquiritin derived from Glycyrrhiza uralensis. These nanoparticles facilitate complete penetration of the cartilage extracellular matrix, exhibit pH-responsive behavior, neutralize reactive oxygen species, and enable controlled drug release, thereby enhancing therapeutic efficacy. The in vitro and in vivo experiments both demonstrate that the composite micro/nanospheres not only inhibit osteoclastogenesis with bone loss in subchondral bone and osteophyte formation, but also mitigate chondrocytes apoptosis, reduce oxidative stress associated with cartilage degeneration, and ameliorate neuropathic hyperalgesia, with the underlying mechanisms being elucidated. The study indicates that such an injectable strategy combining organic biomaterials with Chinese medicine holds substantial promise for the treatment of early osteoarthritis.

Investigating the relationship between radiographic joint space width loss and deep learning-derived magnetic resonance imaging-based cartilage thickness loss in the medial weight-bearing region of the tibiofemoral joint

ObjectiveTo investigate the relationship between measures of radiographic joint space width (JSW) loss and magnetic resonance imaging (MRI)-based cartilage thickness loss in the medial weight-bearing region of the tibiofemoral joint over 12–24 months. To stratify this relationship by clinically meaningful subgroups (sex and pain status). DesignWe analyzed a subset of knees (n ​= ​256) from the Osteoarthritis Initiative (OAI) likely in early stage OA based on joint space narrowing (JSN) measurements. Natural logarithm transformation was used to approximate near normal distributions for JSW loss. Pearson Correlation coefficients described the relationship between ln-transformed JSW loss and several versions of deep learning-derived MRI-based cartilage thickness loss parameters (minimum, maximum, and mean) in subregions of the femoral condyle, tibial plateau, and combined femoral and tibial regions. Linear mixed-effects models evaluated the associations between the ln-transformed radiographic and MRI-derived measures including potential confounders. ResultsWe found weak correlations between ln-transformed JSW loss and MRI-based cartilage thickness ranging from R ​= ​−0.13 (p ​= ​0.20) to R ​= ​0.26 (p ​< ​0.01). Correlations were higher (still poor) among females compared to males and painful compared to non-painful knees. Model results showed weak associations for nearly all MRI-based measures, ranging from no association to β (95% CI) ​= ​0.25 (0.11, 0.39). Associations were higher among females compared to males and minimal differences between painful and non-painful knees. ConclusionsDespite its recommended use in disease-modifying OA drug clinical trials, results suggest that JSW loss is an ineffective proxy measure of cartilage thickness loss over 12–24 months and within a localized region of the tibiofemoral joint.

Effect of Cellular Dosage of Bone Marrow Aspiration Concentrate on the Radiological Outcomes in Knee Osteoarthritis: A Phase I Dose-Escalation Study.

Knee osteoarthritis(KOA), a chronic degenerative disease, significantly impairs quality of life due to pain and mobility limitations. Traditional treatments focus on symptom management without addressing the underlying disease progression, leading to a growing interest in regenerative medicine approaches. Bone marrow aspirate concentrate (BMAC), rich in mesenchymal stem cells and growth factors, has shown potential for cartilage repair and symptom relief in KOA. Despite promising outcomes, the optimal BMAC dosage for knee OA treatment remains undetermined. This study aims to evaluate the radiological outcomes of varying BMAC dosages in knee OA treatment. This prospective controlled dose-escalation study involved 75 patients with early-stage knee OA, categorized into three groups based on BMAC dosage administered 10x106 cells (low-dose group), 50×106 cells (medium-dose group), or 100x106 cells (high-dose group). All the patients underwent a single intra-articular injection of BMAC and were monitored over a year. The primary outcomes include magnetic resonance observation of cartilage repair tissue (MOCART 2.0) score to assess the cartilage. We noted significant improvement in the overall MOCART score (p=0.027) and subchondral change sub-score (p=0.048) and defect filling sub-score (p=0.025) in the medium- and high-dose cohorts compared to the low-dose cohort at 1year follow-up. Although we noted positive correlation between the clinical and radiological outcome (r=0.43), we did not find any significant different in the clinical outcome between the treatment groups. BMAC for OA knee resulted in significant improvement in the radiological scores compared to the baseline. Medium and high doses of BMAC result in significantly higher radiological scores compared to low-dose BMAC at 1year. However, the radiological improvement did not translate into functional improvement, irrespective of the dosage administered at 1year. Further research is necessary on the long-term outcomes to understand and optimize the dosing strategy based on clinico-radiological results.

Effects of Germanium embedded fabric on the chondrogenic differentiation of adipose derived stem cells

Osteoarthritis (OA) is a clinical state which is identified by the degeneration of articular cartilage. OA is a common condition (>500 millions of people affected worldwide), whose frequency is anticipated to continue to rise (> 110 % increase worldwide since 2019). The treatment for early-stage OA is based on a combination of therapeutic approaches, which can include regenerative medicine based on Adipose Derived Stem Cells (ADSCs). Germanium embedded Incrediwear® functional Cred40 fabric has been shown to have positive effects on OA clinically and is envisaged to give encouraging effects also on tissue regeneration. Still, the biological mechanisms underlying this therapeutic modality have not yet been fully defined. We tested the hypothesis that Germanium-embedded Incrediwear® functional Cred40 fabric could enhance chondrogenic differentiation. To this purpose, we applied Incrediwear® to human adipose-derived stem cells (hADSCs) induced to chondrogenic differentiation in vitro. Chondrogenic markers (ACAN, SOX9, RUNX2, COL2A1, COL10A1) were quantified following 21 days of treatment. We also assessed extracellular matrix (ECM) deposition (specifically Collagen and glycosaminoglycans (GAGs)) using Alcian Blue and Sirius Red staining.Here, we provide pilot data to demonstrate that Germanium-embedded Incrediwear® functional Cred40 fabric can enhance hADSCs chondrogenic differentiation and maturity and potentially induce events of cartilage regeneration.

Controlled Release of Ceria and Ferric Oxide Nanoparticles via Collagen Hydrogel for Enhanced Osteoarthritis Therapy.

Osteoarthritis (OA), characterized by chronic inflammation and cartilage degeneration, significantly affects over 500 million people globally. Nanoparticles have emerged as promising treatments for OA; however, current strategies often employ a single type of nanoparticle targeting specific disease stages, limiting sustained therapeutic efficacy. In this study, a novel collagen hydrogel is introduced, thiol crosslinked collagen-cerium oxide-poly(D,L-lactic-co-glycolic acid) microspheres encapsulating nanoparticles (CSH-CeO2-pFe2O3), designed for the controlled release of cerium oxide (CeO2) and ferric oxide (Fe2O3) nanoparticles for comprehensive OA management. The sulfhydryl cross-linked collagen matrix embeds CeO2 nanoparticles and poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres encapsulating Fe2O3 nanoparticles. The CSH-CeO2-pFe2O3 hydrogel exhibits enhanced mechanical strength and remarkable injectability, along with a significant promotion of cell adhesion, proliferation, and chondrogenic differentiation. Notably, the hydrogel demonstrates intelligent responsiveness to high levels of reactive oxygen species, initiating the rapid release of CeO2 nanoparticles to address the intense inflammatory responses of early-stage OA, followed by the sustained release of Fe2O3 nanoparticles to facilitate cartilage regeneration during the proliferative phase. In a rat model with cartilage defects, the hydrogel significantly alleviates inflammation and enhances cartilage regeneration, holding substantial potential for effectively managing the pathologically complex OA.

Intra-articular sprouting of nociceptors accompanies progressive osteoarthritis: comparative evidence in four murine models.

Knee joints are densely innervated by nociceptors. In human knees and rodent models, sprouting of nociceptors has been reported in late-stage osteoarthritis (OA). Here, we sought to describe progressive nociceptor remodeling in early and late-stage OA, using four distinct experimental mouse models. Sham surgery, destabilization of the medial meniscus (DMM), partial meniscectomy (PMX), or non-invasive anterior cruciate ligament rupture (ACLR) was performed in the right knee of 10-12-week old male C57BL/6 NaV1.8-tdTomato mice. Mice were euthanized (1) 4, 8 or 16 weeks after DMM or sham surgery; (2) 4 or 12 weeks after PMX or sham; (3) 1 or 4 weeks after ACLR injury or sham. Additionally, a cohort of naïve male wildtype mice was evaluated at age 6 and 24 months. Mid-joint cryosections were assessed qualitatively and quantitatively for NaV1.8+ or PGP9.5+ innervation. Cartilage damage, synovitis, and osteophytes were assessed. Progressive OA developed in the medial compartment after DMM, PMX, and ACLR. Synovitis and associated neo-innervation of the synovium by nociceptors peaked in early-stage OA. In the subchondral bone, channels containing sprouting nociceptors appeared early, and progressed with worsening joint damage. Two-year old mice developed primary OA in the medial and the lateral compartment, accompanied by nociceptor sprouting in the synovium and the subchondral bone. All four models showed increased nerve signal in osteophytes. These findings suggest that anatomical neuroplasticity of nociceptors is intrinsic to OA pathology. The detailed description of innervation of the OA joint and its relationship to joint damage might help in understanding OA pain.

Fluoroscopy: Taking a closer look at joint motion in osteoarthritis

BackgroundKnowledge of joint biomechanics is crucial for understanding the pathophysiology of osteoarthritis (OA). Biomechanical changes, especially in early-stage OA, are subtle and therefore require highly accurate and precise ways of measuring joint loading (i.e., forces) and kinematics (i.e., motion). Most OA research investigating kinematics to date using conventional measurement methods, has been restricted either to measures of functional, weight-bearing activities with limited precision, or to highly precise measures of non-functional activities. X-ray fluoroscopy, however, is a medical imaging modality that can be used to precisely measure high-speed dynamic human movement in vivo under weight-bearing conditions. ObjectiveTo illustrate the potential of fluoroscopy to measure human movement and study joint biomechanics in OA by highlighting several exemplary applications in studies on knee OA. DesignWe searched PubMed to identify a selection of relevant studies with fluoroscopic evaluation of joint mechanics in individuals with, or at risk of developing, knee OA. ResultsFluoroscopy has been utilized in biomechanical studies in populations with early stages of knee OA or at risk of developing knee OA, as well as in studies evaluating conservative treatment strategies for knee OA. Due to its ability to capture highly accurate and precise kinematic measures, fluoroscopy holds great promise in providing new insights in the role of biomechanics in OA pathogenesis. ConclusionsThe use of fluoroscopy in larger cohorts and longitudinal (interventional) studies may lead to more robust and generalizable results and could clarify the mediation pathways of joint biomechanics in the onset and progression of OA.

Three-gene signature revealing the dynamics of lymphocyte infiltration in subchondral bone during osteoarthritis progression

Osteoarthritis (OA), a degenerative joint disorder, has an unclear immune infiltration mechanism in subchondral bone (SCB). Thus, this study aims to discern immune infiltration variations in SCB between early- and late-stages of OA and identify pertinent biomarkers. Utilizing the GSE515188 bulk-seq profile from the Gene Expression Omnibus database, we performed single-sample gene-set enrichment analysis alongside weighted gene co-expression network analysis to identify key cells and immune-related genes (IRGs) involved in SCB at both stages. At the meanwhile, differentially expressed genes (DEGs) were identified in the same dataset and intersected with IRGs to find IR-DEGs. Protein-protein interaction network and enrichment analyses and further gene filtering using LASSO regression led to the discovery of potential biomarkers, which were then validated by ROC curve analysis, single-cell RNA sequencing, qRT-PCR, western blot and immunofluorescence. ScRNA-seq analysis using GSE196678, qRT-PCR, western blot and immunofluorescence results confirmed the upregulation of their expression levels in early-stage OA SCB samples. Our comprehensive analysis revealed lymphocytes infiltration as a major feature in early OA SCB. A total of 13 IR-DEGs were identified, showing significant enrichment in T- or B-cell activation pathways. Three of them (CD247, POU2AF1, and TNFRSF13B) were selected via the LASSO regression analysis, and results from the ROC curve analyses indicated the diagnostic efficacy of these 3 genes as biomarkers. These findings may aid in investigating the mechanisms of SCB immune infiltration in OA, stratifying OA progression, and identifying relevant therapeutic targets.

Time-Dependent Effect of Eggshell Membrane on Monosodium-Iodoacetate-Induced Osteoarthritis: Early-Stage Inflammation Control and Late-Stage Cartilage Protection.

Osteoarthritis (OA) is a chronic degenerative joint disease that causes chronic pain, swelling, stiffness, disability, and significantly reduces the quality of life. Typically, OA is treated using painkillers and non-steroidal anti-inflammatory drugs (NSAIDs). While current pharmacologic treatments are common, their potential side effects have prompted exploration into functional dietary supplements. Recently, eggshell membrane (ESM) has emerged as a potential functional ingredient for joint and connective tissue disorders due to its clinical efficacy in relieving joint pain and stiffness. Despite promising clinical evidence, the effects of ESM on OA progression and its mechanism of action remain poorly understood. This study evaluated the efficacy of Ovomet®, a powdered natural ESM, against joint pain and disease progression in a monosodium iodoacetate (MIA)-induced rodent model of OA in mice and rats. The results demonstrate that ESM significantly alleviates joint pain and attenuates articular cartilage destruction in both mice and rats that received oral supplementation for 5 days prior to OA induction and for 28 days thereafter. Interestingly, ESM significantly inhibited mRNA expression levels of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as inflammatory mediators, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase in the knee joint cartilage at the early stage of OA, within 7 days after OA induction. However, this effect was not observed in the late stage at 28 days after OA induction. ESM further attenuates the induction of protein expression for cartilage-degrading enzymes like matrix metalloproteinase (MMPs) 3 and 13, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), in the late-stage. In addition, MIA-induced reduction of the protein expression levels of cartilage components, cartilage oligomeric matrix protein (COMP), aggrecan (ACAN) and collagen type II α-1 chain (COL2α1), and cartilage extracellular matrix (ECM) synthesis promoting transcriptional factor SRY-Box 9 (SOX-9) were increased via ESM treatment in the cartilage tissue. Our findings suggest that Ovomet®, a natural ESM powder, is a promising dietary functional ingredient that can alleviate pain, inflammatory response, and cartilage degradation associated with the progression of OA.