骨科领域文献阅读汇编

The purpose of this study was to evaluate the association between systemic low bone mineral density (BMD) and subchondral insufficiency fracture (SIF) of the knee in women, and to explore whether this association is modified by radial meniscal tears. In this case-control study, women with and without MRI-confirmed SIF who had available dual-energy X-ray absorptiometry T-score measurements were included. Systemic BMD was categorized using T-scores. Multivariable logistic regression models with BMD as the exposure and SIF as the outcome, adjusting for age and body mass index were fitted. An exploratory stratified analysis to assess potential effect modification by meniscal radial tear status was also conducted. A total of 121 women with SIF (mean age, 69.1 ± 7.5 [standard deviation] years) and 124 controls (70.4 ± 8.3 [standard deviation] years) were analyzed. After adjustment, osteoporosis was associated with higher odds of SIF (odds ratio [OR], 2.29; 95% confidence interval [CI]: 1.03-5.09), whereas osteopenia (OR, 1.33; 95% CI: 0.69-2.55) showed no significant association. In exploratory stratified analysis to test for effect modification, there were no significant interactions between low BMD and radial root tears (P-interaction = 0.178). However, small strata likely limited the power to detect a significant effect modification, as evidenced by overlapping wide 95% CIs. Osteoporosis is associated with higher odds of SIF of the knee in women, while osteopenia is not.

Although exocrine pancreatic insufficiency (EPI) is thought to be common in type 1 diabetes, little is known about the relationship of EPI with type 1 diabetes parameters or food intake and abdominal complaints. Characterising individuals with EPI could help prevent EPI-related complications such as malabsorption and osteoporosis. In a cross-sectional cohort of 443 individuals with type 1 diabetes (62% female, median age 42 years [IQR 29-54], mean BMI 25±4 kg/m2, median diabetes duration 16 years [IQR 6-29]), we associated faecal elastase (FE) levels, as a marker of EPI, with type 1 diabetes parameters and clinical features, using linear and Poisson regression models. The mean FE level (±SD) was 349.5±146.8 µg/g faeces. A number of variables were independently associated with lower FE levels: older age (-10.97 µg/g faeces per 10 years; 95% CI -21.02, -0.92), longer diabetes duration (-13.09 µg/g per 10 years; 95% CI -23.54, -2.64), higher HbA1c (-1.44 mmol/mol per 1 SD increase in FE levels, 95% CI -2.59, -0.30), male sex (-54.07 µg/g; 95% CI -81.41, -26.73) and smoking (-85.06 µg/g; 95% CI -128.52, -41.60). In a linear analysis, we found no evidence of associations between FE levels and markers of residual beta cell function, liver disease, macronutrient intakes or gastrointestinal complaints. Using a cut-off of 200 µg/g faeces, 76 individuals (17%) were found to have EPI, which was associated with a 4.31 mmol/mol (0.39%) higher HbA1c (95% CI 1.35, 7.26), an 8% higher mean glucose (95% CI 2, 14), a 9% lower fibre intake (95% CI 1, 17) and an 8% lower energy intake (95% CI 1, 15). The lack of evidence for associations with clinical parameters in this relatively healthy population of individuals with type 1 diabetes does not support the use of FE for routine screening for EPI. However, the high prevalence of low FE levels and their association with lower food intake and higher glucose levels justify a need for clinical awareness for EPI and its complications, especially in individuals with long diabetes duration.

Pharmacological targets supported by genetic evidence demonstrate significantly higher success rates in clinical development. Osteoporosis (OP) represents a major global health burden; however, the causal plasma proteome underlying OP remains largely unexplored, limiting the discovery of effective circulating biomarkers and therapeutic agents. This study aimed to conduct a comprehensive proteome-wide analysis to construct a causal map of plasma proteins for OP and to identify high-confidence therapeutic targets with translational potential. We performed a proteome-wide Mendelian randomization (PW-MR) analysis by integrating large-scale GWAS meta-analysis data (18,008 OP cases and 928,650 controls) with cis-acting protein quantitative trait loci (pQTLs) derived from the deCODE and UKB-PPP cohorts. To ensure robustness, we employed orthogonal validation approaches, including colocalization analyses, summary data-based Mendelian randomization (SMR), and single-cell transcriptomic mapping. We identified 144 plasma proteins causally associated with OP, encompassing two novel susceptibility loci (HOXC5 and HBQ1) and five previously unreported candidates (NUDT2, NUB1, TNFSF8, UNG, and MXRA8). Notably, single-cell mapping revealed that NUDT2 is specifically enriched in osteoprogenitor cells, distinct from other identified targets. These findings delineate the first causal blueprint of the OP plasma proteome. NUDT2 is highlighted as a plausible metabolic regulator of bone formation. Collectively, this study provides a valuable resource for precision diagnostics and accelerates the development of novel therapeutics for osteoporosis.

To gain insight into higher fracture risk in individuals with type 2 diabetes, we determined the association of type 2 diabetes glycemic status and severity with longitudinal changes in peripheral bone density and microarchitecture. We conducted a longitudinal study of 769 participants from the Framingham Study who underwent high-resolution, peripheral, quantitative computed tomography (HR-pQCT) at the tibia and radius, in 2012-2016 and 2021-2023 (mean 8-year follow-up). Linear regression models estimated mean 8-year percent changes in bone measures, across indicators of diabetes severity, adjusting for age, sex, weight, and height. The mean age was 67 ± 7 years, and 59% of participants were women. More than half (57%) were normoglycemic (fasting plasma glucose [FPG] <100 mg/dL, not on any treatment), 31% had prediabetes (100 ≤ FPG ≤125 mg/dL), and 12% had type 2 diabetes (FPG >125 mg/dL or on treatment). Adjusted mean percent changes in HR-pQCT bone measures were similar across diabetes severity, including glycemic status, use of diabetes medications, duration of diabetes, and HbA1c. For example, cortical volumetric bone mineral density at the radius changed by -1.50% (95% CI -2.43, -0.56) in type 2 diabetes and -1.96% (-2.53, -1.39), in prediabetes, compared with -2.42% (-2.86, -1.97) in normoglycemia (reference group; all P > 0.05). The magnitude of peripheral bone loss over 8 years did not differ between individuals with type 2 diabetes and those with normoglycemia, suggesting that bone deterioration alone does not explain the higher fracture risk in older adults with type 2 diabetes. Future studies should address other contributors to skeletal fragility.

Exhaustion of skeletal stem and progenitor cells (SSPCs) drives age-related delays in fracture repair, yet the upstream regulators of SSPC maintenance are unclear. We identify that core-binding factor β (Cbfβ) in bone marrow Adipoq+ cells (BMACs) is essential for maintaining SSPC number and function. Cbfβ deletion in BMACs (CKO) leads to SSPC depletion, including periosteal populations, and impairs bicortical fracture healing in mice. Multi-omics (RNA-seq, CUT&Tag-seq, and ATAC-seq) reveal that Cbfβ preserves chromatin accessibility at DNA repair loci, maintaining genomic stability, preventing BMAC senescence, and mitigating the senescence-associated secretory phenotype (SASP). Senolytic therapy alleviates BMAC senescence, restores SSPC populations, and improves bone repair in CKO mice. In both humans and mice, Cbfβ expression declines with aging, accompanied by increased BMAC senescence. AAV-mediated Cbfβ overexpression restores aging-related bone repair and SSPC decline. These findings reveal a novel mechanism in which Cbfβ in BMACs regulates SSPC maintenance via a senescence/SASP axis, offering a potential therapeutic strategy for age-related bone repair deficits.

Vitamin D and its receptor (VDR) are essential for liver homeostasis and bone development, and their dysfunction has been implicated in cirrhosis-associated osteoporosis. This study aimed to elucidate the molecular mechanisms linking hepatic injury to bone fragility. We examined VDR dysfunction in cirrhotic patients and in a murine model of cirrhosis. Hepatocyte-specific VDR knockout mice were used to determine the contribution of hepatic VDR to bone loss during cirrhosis. Analysis of UK Biobank data, a Chinese patient cohort, and murine cirrhosis models demonstrated that reduced serum 25-hydroxyvitamin D (25-OHD) correlates with hepatic fibroinflammation and low bone mass. However, vitamin D3 supplementation failed to restore bone density, indicating noncanonical VDR signaling in bone homeostasis. Hepatic VDR expression declined with progressive fibrosis, and hepatocyte-specific VDR deletion exacerbated trabecular bone loss through enhanced osteoclastogenesis without altering bone formation. Mechanistically, VDR deficiency upregulated hepatocyte fibronectin (FN1), which trafficked to bone marrow and activated osteoclasts via integrin αv. Serum FN1 levels were elevated in cirrhosis patients, correlated with reduced vertebral bone density, and associated with osteoclast activity in mice. Genetic ablation or hepatocyte-specific knockdown of FN1 attenuated bone resorption and improved trabecular architecture. Pharmacologic inhibition of the FN1-integrin αv pathway with CWHM12 reduced osteoclast activity, rescued bone mass, and concurrently ameliorated hepatic fibrosis. These findings establish hepatic VDR as a central modulator of cirrhosis-associated osteoporosis through FN1-mediated integrin signaling. Targeting the VDR-FN1-integrin αv axis offers a dual therapeutic opportunity for managing both hepatic fibrosis and osteoporosis in cirrhosis.

The purpose of this study was to evaluate the relationship between subchondral insufficiency fracture (SIF) of the knee and radial meniscal tears on magnetic resonance imaging (MRI) and to examine within the medial compartment the potential mediating role of meniscal extrusion in this relationship. A retrospective matched case-control study of knee MRI examinations obtained from November 2021 to November 2024 was performed. MRIs were reviewed for SIF, meniscal tear morphology, and meniscal extrusion grade. Associations between radial tears and SIF (overall and medial compartment) were evaluated using conditional logistic regression adjusted for age, sex, and body mass index. Medial-compartment mediation was examined using a natural effects model with medial meniscal extrusion as the mediator. The cohort included 343 patients with SIF (65.4 ± 10.1 [standard deviation] years; 226 women) and 343 patients without SIF (66.4 ± 10.0 [standard deviation] years; 224 women). Compared with knees without radial tears, odds of SIF were higher in the presence of radial root tears (odds ratio [OR], 7.62; 95% confidence interval [CI]: 4.40-13.21) and radial non-root tears (OR, 5.26; 95% CI: 2.48-11.15), with similar findings in the medial compartment. In mediation analysis, medial radial root tears showed an indirect association with medial SIF through medial meniscal extrusion (OR, 1.46; 95% CI: 1.16-1.84), accounting for 16.6% of the total effect. Radial root and non-root tears are strongly associated with SIF on MRI, particularly in the medial compartment. Meniscal extrusion explained a small proportion of this association, suggesting that additional biomechanical pathways are likely in play.

Meniscal injury is a leading cause of early-onset osteoarthritis, yet regenerative options remain limited. This study investigates a nonwoven polyethylene terephthalate (PET) scaffold for meniscus tissue engineering and assesses its capacity to support mesenchymal stromal cell (MSC) proliferation and chondrogenic differentiation under dynamic loading. Human MSCs are seeded onto PET scaffolds (400-420 g/m2, 85% porosity) and cultured for up to 21 days under basal medium (Ctr), chondrogenic differentiation conditions (ChD), or ChD combined with dynamic loading (ChD + Dyn, 12% strain, 1 Hz, 1 h/day, 5 days/week). PET scaffolds support uniform MSC adhesion and colonization. Compared with ChD alone, ChD+Dyn significantly increases cell proliferation and transiently upregulated chondrogenic markers (SOX9, ACAN, COL1A1, COL2A1) while suppressing the hypertrophic marker COL10A1. Although collagen deposition and construct biomechanics remained unchanged over 21 days, glycosaminoglycan accumulation was reduced in the ChD + Dyn group compared with ChD. RNA sequencing revealed distinct mechanosensitive transcriptional signatures induced by dynamic loading, particularly in genes associated with extracellular matrix remodeling, mechanotransduction, and developmental signaling pathways. These findings demonstrate that nonwoven PET provides a mechanically robust scaffold for meniscus tissue engineering and that dynamic loading promotes MSC proliferation while transiently regulating chondrogenic differentiation and mechanoadaptive matrix remodeling toward a meniscus-like phenotype.

Synovitis-driven inflammation and oxidative stress are key drivers of osteoarthritis (OA) progression. As a master regulator of antioxidant and anti-inflammatory defenses, nuclear factor erythroid 2-related factor 2 (Nrf2) represents a promising therapeutic target. However, current strategies for Nrf2 activation remain limited in achieving durable synovial gene expression and pathology-adaptive release. Here, we developed an injectable inflammation-responsive nanocolloidal hydrogel enabling sustained and on-demand Nrf2 activation within OA joints. The hydrogel was fabricated by crosslinking polyvinyl alcohol (PVA) with phenylboronic acid (PBA)-functionalized nanoparticles encapsulating Nrf2 plasmids. Dynamic boronate ester linkages between PBA and PVA enabled rapid in situ gelation after intra-articular injection. In the ROS-enriched inflammatory microenvironment of OA, cleavage of boronate ester bonds triggered the release of Nrf2 plasmid-loaded nanoparticles. The released nanoparticles were efficiently internalized by fibroblast-like synoviocytes (FLSs) and promoted Nrf2 expression, thereby suppressing oxidative stress and inflammatory responses. In ACLT-induced OA mice, the hydrogel markedly alleviated synovial inflammation, preserved cartilage matrix, and reduced the OARSI score by approximately 70%. These findings highlight its potential as a promising strategy for inflammation-adaptive gene regulation in OA therapy.

Osteoarthritis (OA) represents a self-sustaining degenerative process characterized by maladaptive interactions among the cartilage, bone, and synovium triads, with current palliative treatments falling short of addressing its pathophysiological intricacies. Recently, injectable hydrogels specifically designed to tackle the distinct challenges of OA have emerged as a potential solution, offering significant advantages over traditional therapies through innovative integration. This review offers a comprehensive examination of the latest advancements in injectable hydrogel-based therapies for managing OA. First, we dissect the molecular and cellular mechanisms that drive OA progression, placing specific attention on microenvironmental dysregulation. Next, we analyze various hydrogel design strategies, such as matrix composition, crosslinking methods, and stimulus-responsive release, that influence mechanical strength and therapeutic precision. Additionally, we discuss the multifunctional potential of engineered hydrogels, particularly their exceptional ability to support targeted drug delivery. Finally, this review emphasizes the novel potential of these engineered systems to address the unique challenges related to OA management while overcoming the limitations of existing therapies, thereby positioning them as transformative tools for future clinical applications.

Recent advancements in dislocation engineering are reshaping the traditional view towards ceramics being brittle. Here, we use KTaO3 (KTO), a perovskite oxide that is newly discovered with room-temperature bulk plasticity, and demonstrate that the seeded dislocations can effectively tune both mechanical and functional properties. We uncover a brittle-ductile-brittle (BDB) transition: low dislocation densities lead to brittle failure, intermediate densities (∼1014 m-2) enable superior compression plastic deformation capacity with strains over 20%, and high dislocation densities (∼1015 m-2) induce brittle fracture again. This dislocation density-dependent non-monotonic mechanical response challenges the traditional behavior of ceramics and offers design opportunities. Furthermore, dislocation densities can monotonically decrease thermal conductivity, revealing a tradeoff between mechanical strength and functionality. The findings reveal a critical threshold of dislocation density in optimizing the performance of functional oxides, and provide a framework for using dislocations to design advanced materials where mechanical durability and enhanced functionality are intertwined.

Tough adhesives require efficient bulk energy dissipation, yet the molecular design principles for achieving this without sacrificing adhesion strength remain a challenge. Here, we report a chain-length regulation strategy for UV-curable acrylate adhesives, in which long polymer strands between cross-linking points generate effective entanglements, thereby promoting bulk energy dissipation during debonding. The resulting adhesives achieve exceptional adhesion strength (23.13 MPa) and ultrahigh adhesion toughness (36.77 kJ m-2). Fracture measurements and digital image correlation show that the long-chain entangled network markedly increases bulk fracture energy by delocalizing crack-tip strain into an enlarged deformation process zone and retarding crack propagation. Chain-dynamics and chain-conformation analyses further confirm the role of entanglement by revealing a broader relaxation spectrum and a much larger releasable conformational length in the long-chain network that enhances bulk energy dissipation. We further demonstrate its application potential and excellent long-term environmental stability, together with a physics-informed prediction of long-term adhesion retention across practical service temperatures. These results establish chain-length regulation as an effective molecular design strategy for strong and tough adhesives.

Hallux rigidus, or osteoarthritis of the first metatarsophalangeal joint (MTPJ), causes pain and functional limitation. No randomized trials have compared surgery with the natural course of the disease. To compare first MTPJ arthrodesis-a widely used surgical intervention-with watchful waiting in reducing walking-related pain in symptomatic hallux rigidus at 12 months after randomization. Single-center, parallel-group, randomized, controlled, superiority trial with 12-month follow-up. (ClinicalTrials.gov: NCT04590313). Orthopedic department of a tertiary care hospital in Finland. Adults aged 40 years or older with radiographically confirmed (Coughlin-Shurnas grade I to III) hallux rigidus with symptoms over a year and a walking pain score of 4 or higher on a numerical rating scale (NRS) of 0 to 10 were eligible. Exclusion criteria included type 1 diabetes mellitus, rheumatoid arthritis, and hallux valgus angle greater than 15°. Participants were randomly assigned in a 1:1 ratio to surgery with first MTPJ arthrodesis using lag-screw and dorsal plating or to watchful waiting. The primary outcome was walking-related pain (NRS of 0 to 10) at 12 months. The prespecified minimal clinically important difference was 1.7 points. Between November 2021 and June 2024, 90 patients were randomly assigned (45 per group). The mean age was 58.1 years, and 89 participants completed the 12-month follow-up. At 12 months, the observed mean walking-related pain was 1.3 in the arthrodesis group and 5.7 in the watchful waiting group (adjusted mean difference, -5.0 points [95% CI, -6.1 to -3.9 points]), exceeding the prespecified minimal clinically important difference and favoring arthrodesis. Single-center design. Among adults aged 40 years or older with painful hallux rigidus, first MTPJ arthrodesis provides a superior and clinically significant reduction in walking-related pain at 12 months compared with watchful waiting. Suomen Lääketieteen Säätiö Foundation, Finland.

The relationship between socioeconomic status and outcomes after hip fracture surgery remains unclear. We aimed to assess the association between individual-level socioeconomic status indicators and mortality after acute hip fracture surgery in Sweden. Cross-linked registry-based cohort study of patients undergoing acute hip fracture surgery in Sweden 2015-20. Co-primary outcomes were 30-day and 2-yr all-cause mortality. Socioeconomic status was defined using four indicators: level of education, income, residential area, and receipt of social services. Attributable fractions were calculated to illustrate the potential population-level distribution of mortality differences across SES categories. There were 58 641 patients included (median age 83 [interquartile range 75-89] yr, 66.1% women). Crude 30-day and 2-yr mortalities were 7.9% (95% confidence interval [CI] 7.7-8.1) and 35.3% (95% CI 34.9-35.7). Level of education showed the strongest association, with a stepwise gradient most pronounced for 2-yr mortality: adjusted odds ratio 1.16 (95% CI 1.08-1.24) for 10-12 yr, 1.20 (95% CI 1.09-1.32) for 9 yr, and 1.25 (95% CI 1.16-1.34) for <9 yr vs >12 yr (all P<0.001). The attributal fraction for 2-yr mortality was 14.0% (standard error 0.022), with an increase in absolute risk of 6.3% (95% CI 4.3-8.2) for >12 yr vs <9 yr of education. Other socioeconomic status factors, except residential area, were also associated with mortality, although less substantially. Individual socioeconomic status was associated with short- and long-term death after acute hip fracture surgery in Sweden, with education showing the strongest relationship. These findings support consideration of individual-level socioeconomic factors in perioperative hip fracture care at the population level.

Fatty infiltration and fibrosis drive poor outcomes after chronic muscle injury. Here, we characterized fibroadipogenic progenitor cell (FAP) subpopulations from healthy and injured human rotator cuff muscle by single-cell RNA sequencing, full-spectrum flow cytometry, and functional assays and found distinct subpopulations, including a preadipogenic population that expresses delta-like noncanonical notch ligand 1 (DLK1+) and a prefibrogenic population that expresses decay-accelerating factor (CD55+). We used in vitro and flow cytometry experiments to show that human FAP lineages displayed unique surface marker expression across adipogenic and fibrogenic differentiation. In chronic human rotator cuff injury, expression of DLK1 RNA and DLK1 protein was decreased compared with that in healthy muscle. Overexpression of DLK1 in primary human FAPs suppressed differentiation into adipocytes in vitro, whereas DLK1 knockdown increased adipogenesis. In an immunodeficient murine model of glycerol-induced acute muscle injury, xenotransplantation of DLK1-overexpressing human FAPs into the injured murine muscle resulted in reduced fatty infiltration after 14 days by histological assessment, supporting a functional role for DLK1 in restraining adipogenesis. Together, we defined molecularly distinct, clinically relevant human FAP subpopulations, established DLK1 as a regulator of adipogenic potential in vivo, and provided a framework to identify pathogenic FAP states that may be used in the pursuit to prevent maladaptive muscle remodeling.