Osteoarthritis and Cartilage

ObjectivesThe inositol phosphatase SHIP2 plays a crucial role in skeletal development and chondrocyte differentiation, and mutations in INPPL1 (encoding SHIP2) cause opsismodysplasia, a chondrodysplasia with marked cartilage abnormalities. We investigated whether SHIP2 contributes to structural joint remodeling in osteoarthritis (OA). MethodsA cartilage-specific conditional knockout of SHIP2 was generated using Ship2fl/fl mice crossed with AggrecanCreERT2 mice. OA was induced at 9 weeks of age via destabilization of the medial meniscus (DMM). Sham surgery served as control. Mice were sacrificed 12 weeks post-surgery. Histological evaluation of articular cartilage, synovium, osteophytes, and subchondral bone was performed. Chondrocyte hypertrophy was assessed by type X collagen (COLX) staining, and SHIP1 was evaluated as a potential compensatory mechanism. ResultsDMM surgery induced OA-like changes in all genotypes, including cartilage damage, synovial inflammation, osteophyte formation, and subchondral bone thickening. However, Ship2cCART-KO mice showed no differences in OA-related parameters compared to control littermates. COLX expression increased following DMM surgery, independent of SHIP2 deletion. SHIP1 protein levels were not elevated in SHIP2-deficient mice. ConclusionThese findings indicate that SHIP2, while essential for cartilage development, does not act as a structural disease modifier in post-traumatic OA, suggesting that within this context, SHIP2 is not required for maintaining adult articular cartilage structure and is unlikely to represent a major therapeutic target for modifying structural disease progression.

ObjectivesMechanical cues are essential for maintaining cartilage function, yet how they integrate with molecular pathways dysregulated in osteoarthritis (OA) remains poorly defined in human tissue. Canonical Wnt signalling influences cartilage biology and cell-matrix interactions, but its role in integrin-dependent mechanoregulation in human cartilage is not fully understood. This study aimed to determine how Wnt activation affects chondrocyte responses to physiological mechanical loading, with a focus on 5{beta}1integrin and cytoskeletal organisation. MethodsHuman cartilage explants from non-OA and OA donors were subjected to short-term physiological cyclic compression. Canonical Wnt signalling was activated with CHIR99021, and integrin-mediated adhesion was modulated using the 5{beta}1 blocking peptide ATN-161 during loading. Chondrocyte responses were assessed by analysing mechanoresponsive and matrix-related gene expression, 5{beta}1 complex formation via proximity ligation assay and actin cytoskeletal organisation by confocal microscopy. ResultsOA chondrocytes exhibited a distinct integrin profile, characterised by increased ITGA5 and ITGB1 but reduced ITGA10 expression. In non-OA cartilage, canonical Wnt activation increased ITGB1 expression and 5{beta}1 integrin complex formation, while mechanical loading further enhanced ITGA5 and ITGB1 transcription under Wnt-activated conditions. Under control conditions, loading induced mechanoresponsive and anabolic gene expression in non-OA cartilage; these responses were attenuated following Wnt-activation and partially restored by 5{beta}1 blockade. Mechanical loading induced F-actin reorganization toward a more cortical distribution across cartilage zones, irrespective of disease status or treatment. Wnt activation did not result in distinct cytoskeletal phenotypes under load, and load-induced actin remodelling was comparable between groups. ConclusionThese findings identify 5{beta}1integrin as a key mediator linking canonical Wnt signalling to altered chondrocyte mechanoresponsiveness in human cartilage. While mechanical loading consistently induced cortical F-actin reorganization, Wnt-associated changes in load responsiveness arose primarily from integrin-dependent mechanisms rather than major alterations in actin organization. This study highlights the complexity of cartilage mechanoregulation and identifies integrin-mediated signaling as important contributors to canonical Wnt-driven alterations in load responsiveness relevant to OA.

ObjectiveInvestigate how Ca2+/calmodulin dependent protein kinase kinase 2 (CaMKK2) orchestrates a catabolic shift in chondrocytes during early osteoarthritis (OA). MethodsCartilage, osteochondral plugs and chondrocytes were collected from patients undergoing total hip arthroplasty or non-OA donors. SOX9 levels were assessed via immunoblotting or immunohistochemistry (IHC). Sox9 levels were also assessed by IHC in knee joints from wild-type (WT) and Camkk2-/- mice that underwent sham or destabilization of medial meniscus (DMM), with or without STO-609 (0.033 mg/kg) treatment. Co-immunoprecipitation followed by mass spectrometry was performed to identify CaMKK2 interacting proteins in chondrocytes. Kinase assays were analyzed by immunoblotting and phosphosites identified by mass spectrometry. Proteasome function was assessed in murine and human chondrocytes lacking or expressing kinase-active or kinase-inactive CaMKK2. ResultsInhibition or loss of CaMKK2 increased SOX9, whereas the expression of kinase-active, not inactive, CaMKK2 reduced Sox9 in human and mouse OA cartilage. Proteomic analysis of CaMKK2 immunoprecipitates revealed the presence of ubiquitin E3 ligase Ubr4 and the 19S proteasome regulatory particle (RP). CaMKK2 kinase activity was dispensable for its interactions with Ubr4, 19S RP, and Sox9-ubiquitin conjugates, and kinase-inactive CaMKK2 attenuated Sox9 degradation in chondrocytes. Further, CaMKK2 phosphorylated the 19S RP ATPase Psmc5 on Ser136, and an intact kinase increased proteasome activity in chondrocytes. ConclusionsOur findings identify CaMKK2 as a dual-function regulator of chondrocyte UPS with a scaffolding role to assemble UPSUbr4-19S RP around polyubiquitinated proteins such as Sox9, and a catalytic role to enhance proteasome function, potentially through Psmc5 phosphorylation, thereby linking chondrocyte inflammatory signaling to Sox9 degradation and cartilage degeneration.

ObjectiveAnterior cruciate ligament (ACL) tears increase the risk for developing posttraumatic osteoarthritis (PTOA). Females have greater risk for both. However, studies defining sex-specific protein responses in human cartilage after ACL injury are lacking. We hypothesize that articular cartilages response to an injurious environment differs depending on sex. DesignWe compared the proteomic profiles of normal cartilage with injured cartilage harvested from the intercondylar area during ACL surgery. Sex-specific injury effects were estimated through contrasts between Injured Male and Normal Male and between Injured Female and Normal Female. Pathway enrichment analysis was done using gene ontology (GO) and compared against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Extracellular matrix (ECM) proteins were further analyzed using the Matrisome AnalyzeR. ResultsFrom the 2,188 proteins identified, males and females shared 1,121 upregulated and 23 downregulated proteins in injured compared to normal cartilage. Analysis of ECM proteins and enriched pathways revealed mostly similar male and female responses to an injurious environment, with evidence of early cartilage remodeling in both sexes. Nevertheless, more than 240 proteins were affected specifically by sex, and significant sex differences were found in inflammation, ECM-related, and metabolic pathways. Males were enriched mostly in "ECM-receptor interaction", while females were enriched in "Citrate cycle (TCA cycle)", "Fatty acid degradation", and "Fatty acid metabolism" pathways. ConclusionArticular cartilage shows signs of remodeling soon after ACL injury, even when only exposed to an injurious environment rather than being physically impacted. Sex differences were observed in inflammation, metabolic pathways, and ECM synthesis.

ObjectiveRecently, alternatives to animal testing, such as new approach methodologies, are being developed in the orthopedic research field; animal models still provide valuable insights into the pathogenesis of knee osteoarthritis (OA). However, commonly used models develop OA much more rapidly and severely than those observed in human patients. We aimed to develop a novel murine model that closely mimics the slow progression of human OA with posterior Cruciate ligament (PCL) rupture. Design12-week-old C57BL/6 mice were induced to PCL-rupture (PCL-R) by manually applying an external tibial posterior translation force. We analyzed joint kinematics, histological observations, and bone structure to confirm the absence of concurrent injury on day 0. Then, joint stability and the pathophysiological progression of knee OA were analyzed at 8, 16, and 34 weeks post-PCL-R. The destabilized medial meniscus (DMM) model was also analyzed to compare the OA progression. ResultsNon-invasive PCL-R intervention induced the complete rupture in the central region of PCL without concurrent injury. The PCL-R group showed larger posterior tibial deviation than the INTACT (P=0.008). Regarding the range of motion in the PCL-R group, there was no limitation in range of motion on day 0, but extension limitations occurred at weeks 16 and 34 weeks. Histologically, articular cartilage degeneration in PCL-R was milder than DMM. In the subchondral bone, micro-CT reconstruction images indicated that, compared with the INTACT group, the DMM group observed progressive subchondral bone formation from 16 weeks post-surgery. In contrast, the PCLR group maintained the subchondral bone structure even at 34 weeks. ConclusionsPCL-R model induced mild abnormal mechanical stress depending on posterior instability, and cartilage degeneration occurred more slowly in this model than in DMM models.

BackgroundPain with movement is common in adults with knee osteoarthritis (OA), but the effect of movement-evoked pain on gait is not well understood. This relationship is vital to understand as gait mechanics are associated with OA initiation and progression. Our current understanding of acute changes in pain and gait stems from extended bouts of walking, however these bouts likely dont represent real-world behavior. Therefore, understanding how gait changes with shorter, more intense bouts of activity may provide valuable insight into the pain experience. MethodsAdults with (n=19) and without (n=19) knee OA wore inertial measurement units (IMUs) while completing bouts of walking before and after two bouts of stair navigation (two flights). We tested whether pain and gait (speed, stride length, and lower extremity joint ranges of motion (ROM)) changed differently between adults with and without knee OA in response to multiple bouts of stair activity. FindingsThere were no significant interactions between group and stair bouts for any variable. When stratifying the OA group by those who did and did not experience pain, those who experienced a change in pain also had a greater change in early stance knee ROM in response to bouts of stairs. InterpretationThe observed changes suggest that knee kinematics may be more sensitive to acute changes in pain than gait speed or stride length. These differences were detectable using IMUs and therefore our results support the use of IMUs to measure concurrent pain and gait mechanics in less controlled and real-world settings.

Introduction Knee pain is a highly prevalent condition in the general population and is more common than knee osteoarthritis. Population-based evidence linking metabolic dysfunction to knee pain remains limited, and data on sex-specific effects are scarce. Therefore, we examined sex-specific associations between metabolic dysregulation and knee pain in a population-based cohort. Method We analyzed data from a population-based cohort of 1,512 adults (mean age 37.2 years at baseline), of whom 250 completed follow-up after a mean of 9.4 years. Metabolic dysfunction was assessed using a continuous MetS severity score (cMetS) derived from waist circumference, triglycerides, HDL cholesterol, fasting glucose, and systolic blood pressure. Knee pain at follow-up was defined using a combined measure based on a standardized question and a body manikin. Logistic regression models were used to examine associations between baseline cMetS and knee pain, including interaction analyses by sex. Results At follow-up, 28.5% of participants reported knee pain. Higher baseline cMetS was associated with increased odds of knee pain in males (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.17-1.69) but not in females (OR 0.94, 95% CI 0.84-1.07), with evidence of interaction by sex (interaction P < 0.001). Findings were consistent across sensitivity analyses. Conclusions These results indicate that metabolic dysfunction is associated with knee pain in males but not in females, suggesting sex-specific mechanisms linking metabolic dysfunction and knee pain.

ObjectiveAdults with knee osteoarthritis often experience movement-evoked pain (MEP), and that pain has the potential to alter gait mechanics and influence disease progression. However, the associations between MEP and gait biomechanics have only been assessed in typical lab settings. Gait mechanics differ in the lab compared to in the real-world, thus it is unknown whether these associations between pain and gait translate to real-world settings. Therefore, this study aimed to measure concurrent changes in MEP and gait mechanics across three days of typical real-world activity. DesignSeventeen participants with self-reported physician-diagnosed symptomatic knee osteoarthritis wore inertial measurement units on their more symptomatic limbs thigh and shank, as well as on both feet for three days of typical activity. Participants were sent 5 automated text messages a day and were instructed to complete a short 3-5 minute walk and self-report their MEP via a Numeric Rating Scale (0-10) during each of the walks. A random coefficients model was used to determine how gait speed, stride length, and knee and ankle range of motion was related to changes in pain intensity. ResultsThe average MEP experienced during the instructed walks was 1.4 {+/-} 1.3 with individual participant average pain intensities ranging from 0 to 4.8. Greater MEP was associated with a 2.7{degrees} decrease in knee range of motion per unit increase in pain (95% CI [-4.8 -0.5], p = 0.02). Seven of the seventeen participants never reported a pain level of 0. Speed, stride length, and ankle range of motion did not differ by pain intensity. ConclusionsIncreases in MEP were associated with decreases in knee range of motion. A 2.7{degrees} decrease in knee range of motion in response to a 1-unit change in pain is meaningful as 5{degrees} is generally considered the threshold for a meaningful difference in joint angles. With a change in pain intensity of 2 being common with daily activity, individuals may be experiencing meaningful changes in knee joint angles regularly. With gait mechanics being associated with disease progression, these daily acute fluctuations in pain may be influencing disease progression rates.

Background: Rheumatoid arthritis is a chronic inflammatory disorder in which exercise is increasingly recognized as an important component of long-term management. Yet, most reviews in this field evaluate the effects of single exercise modalities, while bibliometric studies primarily identify publication trends and research hotspots without showing whether highly visible themes also represent coherent and comparatively mature evidence domains. Methods: We searched the Web of Science Core Collection for publications on exercise interventions in rheumatoid arthritis from 2016 to 2025. CiteSpace (6.4.1) and VOSviewer (1.6.20) were used to analyze publication growth, collaboration networks, keyword co-occurrence, thematic clusters, and burst terms. We then applied structured content coding in Excel 2021 to classify exercise modalities, outcome domains, and mechanistic topics, and integrated these findings into a visual evidence-distribution profile. Results: Publication output increased from 16 studies in 2016 to 37 in 2025. The United States led in productivity, Karolinska Institutet was the most prolific institution, and Kitas, Duda, and Metsios were among the most influential authors. Keyword analyses identified a shift from function- and disease-focused themes toward quality of life, risk factors, and comprehensive management. The integrated analysis revealed an uneven evidence structure: aerobic and resistance training accounted for the most concentrated and recurrently studied exercise-outcome domains, whereas mind-body and water-based interventions formed visible but methodologically heterogeneous clusters. Newer modalities, including blood flow restriction training and high-intensity interval training, showed growing prominence but limited depth of evidence. Conclusion:Exercise research in rheumatoid arthritis has evolved toward broader and more patient-centered management targets, but the field remains imbalanced across intervention types and outcome domains. This study demonstrates the value of combining bibliometric mapping with structured content analysis to distinguish thematic visibility from evidentiary coherence in heterogeneous intervention fields and may offer a transferable analytical framework for research evaluation beyond rheumatoid arthritis. Keywords: Rheumatoid Arthritis; Exercise Intervention; Bibliometrics; Content Analysis; Rehabilitation

Background. A substantial minority (~20%) of patients fail to achieve meaningful pain reduction following surgery intended to relieve pain. Risk is elevated in patients with nociplastic pain features, but available self-report measures were not designed for pre-surgical screening. We aimed to develop a brief, data- driven screener for poor analgesic response to surgery. Methods. Participants were recruited from tertiary orthopedic and chronic pelvic pain clinics. Total hip arthroplasty participants had Kellgren-Lawrence grades III-IV with hip pain greater than or equal to 1 year; hysterectomy participants had chronic pelvic pain greater than or equal to 6 months. The primary outcome was a 50% reduction in worst pain at six months. Items were selected via elastic net regression with k-fold cross-validation from 68 candidates. Results. Of 428 participants (81% female; mean age 51), 35% failed to achieve a 50% pain reduction. The resulting 11-item screener - the GenerAlized sensory sensitivity for sUrGical rEsponsiveness (GAUGE) - comprises pain across seven body regions and four symptom items measuring interoception (nausea, numbness/tingling) and exteroception (sensitivity to sound, sensitivity to odors). GAUGE outperformed the Central Sensitization Inventory, Fibromyalgia Survey Criteria, and PainDETECT for predicting surgical non-response (RR 1.535, 95% CI 1.342-1.55; AUC 0.738; sensitivity 0.741, specificity 0.635) and for predicting Patient Global Impression of Change. In an independent validation cohort of 54 total knee arthroplasty patients, GAUGE outperformed the Fibromyalgia Survey Criteria in predicting pain severity at six-months. Conclusions. GAUGE is a data-driven, theoretically grounded screener for poor analgesic response to surgery, with potential utility for pre-surgical counseling and clinical trial enrichment.

Introduction: Osteoarthritis (OA) is a chronic joint disease, often leading to pain, joint stiffness and impaired function. The first metatarsophalangeal (MTP-1) joint is the most frequently affected joint in foot OA. Footwear interventions might have potential to reduce pain for people with MTP-1 joint OA. The aim of this study is to determine the effectiveness and cost-effectiveness of orthopaedic modifications to off-the-shelf footwear in addition to usual care, compared to usual care alone, for people with MTP-1 joint OA. Methods and analyses: We perform a pragmatic, non-blinded, two-armed, parallel-group, randomised controlled trial (RCT). A total of 136 people with MTP-1 joint OA and presence of foot pain are recruited. Participants are randomised to orthopaedic modifications to off-the-shelf footwear in addition to usual care or to usual care alone. The footwear modifications comprise a combination of sole-stiffening, rocker sole adjustments and custom-made insoles. During a 12-month follow-up period, participants receive monthly questionnaires. Primary outcomes include walking pain at 6-month follow-up and quality-adjusted life years and societal costs at 12-month follow-up. Secondary outcomes include walking pain at 12-month follow-up and foot health, physical activity level, patient acceptability and self-reported recovery at 6- and 12-month follow-up. Intention-to-treat and per-protocol analyses will be performed using (generalised) linear mixed models. Ethics and dissemination: The study is approved by the local Medical Ethics Committee of the Erasmus MC University Medical Center Rotterdam, The Netherlands (MEC-2024-0615). Prior to study participation, participants provide informed consent. Results will be disseminated amongst researchers through peer-reviewed scientific articles and presentations at conferences; and amongst people with MTP-1 joint OA and healthcare professionals through layman articles in newsletters, on websites and on social media. Discussion: This is the first RCT to investigate the effectiveness and cost-effectiveness of orthopaedic modifications to off-the-shelf footwear in addition to usual care, compared to usual care alone for people with MTP-1 joint OA. Study findings will support healthcare professionals in making substantiated decisions in the treatment of people with MTP-1 joint OA.

Background: Spinal pain, including neck pain and low back pain (LBP), is a common musculoskeletal condition and major contributor to disability worldwide. Evidence comparing disability, fatigue and mental health across acute and chronic stages remains limited, particularly in conflict-affected and low-resource settings. This study assessed these outcomes among patients with acute and chronic neck pain and LBP in the Gaza Strip. Methods: A comparative cross-sectional study was conducted among 410 adults attending outpatient physical therapy at Nasser Medical Complex, Khan Younis, Gaza Strip. Participants included 204 with neck pain and 206 with LBP, classified as acute neck pain (n=101), chronic neck pain (n=103), acute LBP (n=102) and chronic LBP (n=104). Disability, fatigue, psychological distress and sleep disturbance were assessed using the Neck Disability Index (NDI)/Oswestry Disability Index (ODI), Fatigue Severity Scale (FSS), Patient Health Questionnaire-4 (PHQ-4) and PROMIS Sleep Disturbance Short Form 8a. Independent t-tests, adjusted linear regression, correlation analyses, clinical-threshold analyses and binary logistic regression were performed. Results: Chronic neck pain and chronic LBP were associated with significantly higher disability, fatigue and psychological distress than acute pain. Chronic neck pain patients had higher NDI, FSS and PHQ-4 scores than acute neck pain patients; chronic LBP patients had higher ODI, FSS and PHQ-4 scores than acute LBP patients (all p<0.001). Sleep disturbance did not differ significantly between groups. Female participants reported higher psychological distress in both pain groups, with higher fatigue in neck pain and higher disability in LBP. Adjusted analyses confirmed that chronic pain status remained associated with higher disability, fatigue and psychological distress. Fatigue was the most consistent factor independently associated with chronic pain status. Conclusions: Chronic spinal pain was associated with greater disability, fatigue and psychological distress than acute spinal pain, while sleep disturbance was common across groups. These findings support early multidimensional assessment, including screening for fatigue and psychological distress. Longitudinal studies are needed to clarify whether these factors contribute to transition from acute to chronic spinal pain.

Patellar osteochondral allograft (OCA) transplantation is widely used to treat large full-thickness cartilage defects, yet long-term failure and reoperation rates remain high. Although surface congruity and osseous integration are emphasized clinically, cartilage thickness and mechanical compatibility between donor and recipient are not considered. Our previous work suggests that cartilage thickness mismatch can amplify local deformation at the graft boundary, potentially compromising graft longevity. This study investigates how combined mismatches in cartilage thickness and mechanical properties influence the local strain environment at the patellar OCA interface. Simplified two-dimensional axisymmetric finite element models of patellar OCA repair were developed in ABAQUS. Donor-to-recipient cartilage thickness ratios ranging from 0.33 to 3.25 were evaluated together with donor-recipient Youngs modulus mismatches (2.5-7.0 MPa). Cartilage was modeled using homogeneous linear elastic and functionally graded material formulations to account for depth-dependent stiffness. A compressive pressure of 1.0 MPa was applied to represent patellofemoral joint loading, and peak compressive and shear strains were quantified at the graft boundary. Cartilage thickness mismatch produced localized high-strain regions (HSR) of compressive and shear strain at the donor-recipient interface that were absent in thickness-matched constructs. Strain amplification increased with both thickness and mechanical property mismatch. Compressive strain exhibited directional asymmetry, with donor-side-thicker configurations producing greater amplification than recipient-side-thicker configurations. Incorporating depth-dependent cartilage stiffness reduced peak strain magnitudes but did not eliminate mismatch-driven strain amplification. These findings demonstrate that cartilage thickness and mechanical disparity can create HSR at the patellar OCA graft boundary that may predispose grafts to impaired integration and long-term failure.

Focal injuries to articular cartilage in load-bearing joints fail to heal and often progress to degeneration, underscoring the need for repair strategies that result in restored cartilage structure and function rather than fibrocartilage formation. Granular extracellular matrix (gECM) hydrogels, flowable grafts composed of densely-packed matrix particles, offer a promising approach but lack long-term functional validation in large-animal models. Here, we developed a flowable gECM hydrogel composed of decellularized cartilage microparticles incorporated within a thiol-functionalized hyaluronan matrix. Proteomic analysis confirmed enrichment of cartilage-specific gECM matrisome components. When implanted into critical-sized femoral condyle defects in a goat model and evaluated 12 months post-implantation, both gECM hydrogel and microdrilling (surgical controls) achieved >80% defect filling. However, in contrast to microdrilling, gECM repair tissue exhibited surface tribological (friction, adhesion) and compressive mechanical properties comparable to native cartilage, with a similar proteoglycan-to-collagen ratio, enrichment of type II collagen, minimal type I collagen (typical of a fibrous scar), improved quantitative MRI metrics, and evidence of lateral cartilage integration and subchondral bone remodeling. Together, these findings demonstrate that a flowable gECM hydrogel supports integrative, cartilage-like repair in a load-bearing joint, supporting advancement of this approach toward clinical translation. One Sentence SummaryA granular ECM hydrogel implanted in a goat condyle provided a robust repair, filling the defect tissue with integrated, hyaline-like cartilage at 12 months.

Post-traumatic osteoarthritis (PTOA) is a common long-term consequence of joint injury and a major cause of chronic pain and disability, yet no disease-modifying therapies are currently available. A central barrier to effective intervention is the persistence of maladaptive synovial inflammation, driven in part by macrophage-mediated signaling that sustains tissue degeneration and pain. Here, we developed a scalable, chemically defined platform to generate human induced pluripotent stem cell (iPSC)-derived anti-inflammatory macrophages (iMac-M2) as an off-the-shelf cell therapy designed to restore joint immune homeostasis after injury. These cells maintained a stable anti-inflammatory phenotype and function under osteoarthritis-relevant inflammatory conditions and suppressed inflammatory and catabolic responses in human joint cell co-culture systems. In a preclinical model of PTOA, intra-articular delivery of iMac-M2 after injury improved functional and structural outcomes while modulating synovial inflammatory and pain-associated transcriptional programs. Treatment was well tolerated, with no evidence of systemic immune activation or ectopic tissue formation. Together, these findings support iPSC-derived macrophage therapy as a clinically translatable immunomodulatory strategy to interrupt early inflammatory drivers of PTOA and preserve joint health following injury. One Sentence SummaryAn iPSC-derived macrophage therapy restores joint balance, protects cartilage, and relieves pain after traumatic joint injury.

Abstract: Objective This study aimed to systematically screen for potential candidate biomarkers and identify therapeutic targets associated with gouty arthritis (GA) through integrated analyses of single-cell and bulk RNA sequencing (RNA-seq) data. Methods The single-cell dataset GSE211783 and the bulk RNA-seq dataset GSE160170 were analyzed using a series of bioinformatic approaches, including cell clustering, differential expression analysis, immune cell infiltration assessment, protein-protein interaction network construction, gene set enrichment analysis, as well as drug sensitivity evaluation. To establish an animal model of GA, monosodium urate crystals were injected intra-articularly into experimental mice. Joint swelling was evaluated, and morphological changes in joint tissues were analyzed through hematoxylin-eosin staining. The presence of TREM1-positive cells was detected by immunohistochemistry and the level of TREM1 protein expression in joint tissues were assessed by Western blotting. Results We identified 102 differentially expressed genes (DEGs) and 14 signaling pathways associated with GA. The PPI network revealed 25 hub genes, of which 17 (including TREM1, TNF, PTGS2, and NLRP3) were highly expressed and 8 (including FCGR3B and CXCR6) showed low expression in the GA samples. These genes correlated significantly with the infiltration levels of macrophages. Among the hub genes, TREM1 was selected for further validation because it correlated significantly with all 14 differential pathways. In animal experiments, GA mice developed marked joint swelling and inflammatory tissue injury, along with a significant increase in TREM1-positive cells and TREM1 protein expression. Conclusion Integrative analysis of single-cell and bulk RNA-seq data identified 102 GA-related DEGs and 14 key pathways, from which 25 hub genes were screened. TREM1 is significantly upregulated in GA and may be linked to macrophage function, providing new insights into biomarker and therapeutic target discovery for GA.

ObjectiveLoss of skeletal muscle mass and performance is a hallmark of ageing. Mitochondrial function has been suggested as a critical determinant of skeletal muscle performance. However, mixed results have been reported regarding mitochondrial function in older individuals. Therefore, the primary objective of this systematic review is to determine whether 31P-MRS-derived {tau}PCr, reflecting mitochondrial oxidative capacity, is reduced in ageing skeletal muscle. MethodsA preregistered systematic literature review was performed using the databases MEDLINE, EMBASE, SPORTDiscus, and Cochrane Central Register of Controlled Trials (CENTRAL). Papers were included if they reported {tau}PCr as measured by 31P-MRS; and studied individuals over 65 years of age in combination with a younger control group. Differences between young and older groups were assessed using random effects meta-analysis. ResultsWe included 20 papers in total, of which 2 measured 2 muscles, 5 focused on the tibialis anterior (TA) muscle, 11 on the calf muscles, 5 on the quadriceps, and 1 on the flexor digitorum longus. No statistically-significant differences were found in {tau}PCr between older and younger adults for all muscles combined (Hedges g=0.11 (p=0.487). Inter-study heterogeneity was high ({tau}2=0.36, I2=72.49%, H2=3.64). Sub-analyses for the individual muscles showed longer {tau}PCr in the quadriceps (g=0.65, p<0.001) in older adults, but shorter {tau}PCr in the TA muscle (g=-0.64, p<0.001). For the calf muscles, no differences were detected between older and young individuals (g=0.20, p=0.377). ConclusionNo uniform age-related decline was found for {tau}PCr when comparing all studies together. Substantial heterogeneity was observed between the individual muscles, with {tau}PCr being prolonged in the upper leg muscles in older adults, but shortened in the tibialis anterior. This suggests more work using standardised settings and well-defined cohorts is needed.

BackgroundThe pivot shift (PS) test is the most specific clinical examination for anterolateral rotational instability in ACL-deficient knees, yet grading remains subjective, as evidenced by poor inter-observer reliability, particularly for Grade 2. Since low-grade (Grade 1) versus high-grade (Grades 2/3) PS is the threshold for recommending lateral extra-articular augmentation, performing the test in awake clinic patients limits grading reproducibility and introduces variability in surgical decision-making. Existing methods to quantify the pivot shift usually require examiner-performed testing under general anaesthesia. No prior approach has ascertained PS grading from a separate patient-performed functional movement. PurposeTo evaluate the feasibility of a machine learning (ML) classifier, trained on kinematic ultrasound bone-tracking signals acquired during a patients sit-stand-sit (SSS) knee movement, to predict their PS grade, and to clinically validate its ability to differentiate low versus high-grade PS. MethodsUltrasound bone-tracking kinematic data were collected during SSS manoeuvres in 23 ACL-injured patients using the GATOR device, and ground truth PS grades (0-3) were assigned under general anaesthesia by fellowship-trained orthopaedic sports surgeons. From the data collected, Leave-one-out cross-validation (LOOCV) was used to train the ML classifier. Clinical SSS data from 6 ACL-deficient patients was used for independent held-out validation of their low-grade (Grade 1) versus high-grade (Grade 2/3) PS. Multiple deep learning architectures (XceptionTime, InceptionTime, FCN, ResNet, ResCNN) and training strategies (including mixup augmentation and supervised contrastive learning) were tested. Performance was measured by one-versus-rest (OVR) AUC under LOOCV and by AUC (low vs high grade PS) from the held-out patient sessions. ResultsThe ML classifier achieved a maximum OVR AUC of 0.928 {+/-} 0.084 under LOOCV. Classifier performance increased with pivot-shift severity: Grade 3 was identified most reliably (AUC ~0.81; sensitivity 0.70-0.80), whereas Grade 2 remained the most challenging boundary (sensitivity 0.20-0.75 across configurations). For the clinically relevant binary classification of low-versus high-grade pivot shift, the classifier generalised well to a completely unseen patient cohort (AUC 0.889; accuracy 0.860; sensitivity 0.850; minimum-class sensitivity 0.767). ConclusionThe study demonstrates that kinematic ultrasound bone-tracking during sit-stand-sit contains transferable information about rotational instability severity in ACL-deficient patients, and represents the first reported approach to predict pivot shift grade from a patient-performed functional movement. The strong cross-validation performance confirms that the signals contain meaningful PS grade-discriminative information, but larger datasets targeting 50-100 sessions per grade will be required to achieve patient-level generalisation and advance this novel rotational instability assessment tool toward full clinical adoption. Level of EvidenceLevel IV, diagnostic feasibility study.

ObjectivesTo investigate the epidemiology of acute sports-related upper-extremity injuries in young athletes, with a particular focus on the frequency, anatomical distribution, injury types, and mechanisms of digit injuries. MethodsThis single-center retrospective observational study included athletes aged [&le;]22 years who sustained acute sports-related upper-extremity injuries between January 2017 and November 2025. Digit injuries were defined as injuries involving the thumb and fingers at or distal to the metacarpophalangeal joint. Injury characteristics, mechanisms, and sports categories were analyzed using descriptive statistics. ResultsA total of 1,219 acute sports-related upper-extremity injuries were analyzed. Digit injuries were the most common injury location, accounting for 412 cases (33.8%), followed by shoulder (30.7%), elbow (17.5%), wrist (14.4%), and palm injuries (3.6%). Jammed finger was the most frequent injury type, comprising 64.8% of digit injuries, followed by fractures (20.1%) and dislocations (5.3%). Most injuries were caused by contact mechanisms (90.3%), with ball contact being the predominant cause (49.5%). Ball sports accounted for 85.4% of all digit injuries. ConclusionsDigit injuries represent the most frequent acute sports-related upper-extremity injuries in athletes aged [&le;]22 years, with jammed finger accounting for the majority of cases. Most injuries were associated with ball contact, highlighting the need for preventive strategies and appropriate initial management for digit injuries in young athletes.

Tissue-level mechanical stimuli are primary drivers of tissue adaptation and can be optimised during conservative treatments to improve treatment outcomes for many highly prevalent musculoskeletal conditions. Current laboratory-based technologies limit our ability to connect conservative interventions such as exercise and movement modification with muscle, joint, and tissue-level mechanics, in natural environments. We introduce a physics-informed neural network (PINN) to estimate clinically relevant biomechanics from smart garments. By accounting for physiological dynamics of neural activation and muscle contraction, the PINN accurately predicted hip joint angles (RMSE <6 degrees), moments (RMSE 0.12 N*m/kg to 0.30 N*m/kg), and joint forces (RMSE 6 to 16%) from three inertial measurement units and four electromyographic sensors. We demonstrated that the trained PINN can be combined with a smart garment to estimate hip biomechanics, in real-time, during a gait retraining intervention aimed at modifying joint loading to treat hip osteoarthritis. The developed PINN and smart garment system may be adapted and generalised for personalised management or rehabilitation of a broad range of musculoskeletal diseases and injuries, in clinical, home, workplace, and sporting environments.