Bone & Joint Research最新文献

Aims: The Oxford Knee Score (OKS) is a 12-item patient-reported outcome measure (PROM), developed for patients who are candidates for total knee arthroplasty (TKA). A prerequisite for a PROM to be considered an adequate measurement instrument is a unidimensional structure as demonstrated by a modern test theory (MTT) model, meaning that each (sub)scale reflects one construct (e.g. pain). However, the structural validity of OKS has only been sparsely evaluated with MTT, and with ambiguous results. This study aimed to assess the structural validity of the Danish OKS. Since the OKS includes items addressing both pain and physical function, it was hypothesized that scores were more accurately reported as two separate subscales.

Methods: OKS responses from a study of 1,059 patients treated with a TKA were obtained. Four random subsamples (each with 400 patients) - female and male, preoperative and three months postoperative - were assessed by confirmatory factor analysis (CFA) and Rasch analysis. CFA model fit was evaluated using the chi-squared statistic and indices of close fit. Rasch fit was evaluated with item fit statistics. Both a one-factor solution and two-factor solutions with scores based on two separate subscales were considered for each subsample.

Results: OKS data did not fit the original unidimensional model of one total score. Reporting OKS data as the two subscales "pain" and "function" improved CFA fit, but model fit was still inadequate. Results were consistent across subsamples.

Conclusion: The structural validity of the Danish OKS is inadequate for evaluating patients awaiting TKA or surgically treated with TKA. OKS data should therefore be interpreted with caution. Randomized treatment studies showing no difference in OKS scores may be reanalyzed based on the two domains to reduce the risk of a potential type-2 error.

Aims: Aseptic loosening of the acetabular cup is one of the main causes of implant failure after total hip arthroplasty (THA). Insight in bone remodelling activity around implants could enable early assessment of implant fixation as a predictor for long-term implant stability. In this study, 18F-fluoride positron emission tomography/CT (PET/CT) is used to quantify longitudinal bone remodelling activity around two different acetabular cup designs.

Methods: A prospective cohort of 14 patients undergoing THA was enrolled. These patients received an uncemented hydroxyapatite-coated cup (n = 6) or an uncemented cup with a porous titanium surface (n = 8). PET/CT scanning was performed postoperatively at three, six, and 12 months. Custom-made software was developed to analyze the longitudinal bone remodelling activity around acetabular cup. A set of points surrounding the cup was semiautomatically defined in the CT scan. For each of these points, the standardized uptake value (SUV) was calculated using the corresponding PET data. These points were used for 3D visualization and quantification of bone remodelling activity by averaging SUVs into segments.

Results: For both acetabular cup designs, the highest SUVs were found in the superolateral region after three months' follow-up, and a significant decrease of SUVs over time was observed. For the titanium cup, the higher SUV in the superolateral region compared to other regions was still apparent after 12 months' follow-up.

Conclusion: A semiautomatic method to evaluate 18F-fluoride PET/CT scans of patients after THA was designed. The technique can be used to analyze and compare longitudinal bone remodelling activity around different acetabular cup designs.

Aims: The aim of this study was to investigate a biomimetic biodegradable cell-free osteochondral scaffold in a clinically relevant large animal model to quantify the early integration and regeneration phases after implantation.

Methods: Bilateral critical-sized osteochondral defects were created in 14 sheep. One defect was filled with the scaffold, whereas the contralateral was left empty. The graft integration and regeneration tissue quality were evaluated at 14 and 30 days of follow-up. In particular, samples were evaluated for inflammation grade according to the ISO 10993-6 international standard biological evaluation of medical devices, macroscopic appearance graded according to a modified Fortier et al scoring system, histological quality according to a modified International Cartilage Repair Society (ICRS) II score, and the new trabecular bone formation with a micro-CT analysis.

Results: At 14 days, a higher defect filling was found in the scaffold group compared to the control in the gross analysis (p < 0.001). Low inflammation was observed in both groups, with a slight increase in the scaffold group at 30 days. The scaffold group had better histological scores, with a significantly higher mean global ICRS II score at 30 days compared to controls (p = 0.031). Finally, the mean percentage of new trabecular bone (BV/TV) was significantly higher in the scaffold group versus the control group, both at 14 days (11.5% (SD 4.5) and 5.2% (SD 2.3), respectively; p = 0.005) and at 30 days (28.0% (SD 8.1) and 8.8% (SD 5.0), respectively; p = 0.002).

Conclusion: The tri-layered biomaterial showed good integration with surrounding tissues and new tissue growth promotion after 14 and 30 days post-surgery, with no safety concerns. In light of the development of appropriate postoperative rehabilitation programmes to prevent the risk of early implant failure while avoiding delays and providing a proper recovery path, this study provides support for the new cartilage field trend for this osteochondral scaffold, suggesting the possibility of safely shortening the postoperative rehabilitation phase after surgery.

Aims: To examine cellular and molecular mechanisms of meniscal degeneration, including matrix degradation and inflammation, and identify therapeutic targets for osteoarthritis interventions.

Methods: Meniscal tissue samples were collected from a total of ten patients. Using a small animal running platform, a mouse model of meniscal injury was established via running training, and the extent of the damage was assessed using histological and immunohistochemical staining. Human meniscal cells and tissues obtained from ten patients undergoing arthroscopic surgery or joint replacement arthroplasty were exposed to mechanical stimuli, mimicking the forces experienced during human running activity using a cyclic stretching system. Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses were performed to evaluate the responses. Transcriptome sequencing was conducted to determine gene expression changes associated with meniscal injuries, and functional alterations were analyzed using the Metascape platform. Rapamycin was administered via knee injections to evaluate its therapeutic effects on meniscal damage.

Results: Histological staining showed progressive meniscal tissue degeneration over time in the high-intensity running group. Transcriptome analysis revealed that the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was markedly enriched in mechanically overstressed meniscal cells. Downstream activation of the mammalian target of rapamycin (mTOR) pathway was confirmed via western blot and immunofluorescence, consistent with the results of the mouse chronic overload model. The subsequent intra-articular administration of rapamycin, a well-established mTOR inhibitor, substantially mitigated meniscal degeneration in mice, a finding corroborated in experiments using human meniscal cells.

Conclusion: These observations demonstrate that prolonged and excessive mechanical stress may contribute to meniscal damage or degeneration through activation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) axis.

Aims: The management of Paprosky IIIB acetabular bone defect is challenging in revision total hip arthroplasty. Custom-made acetabular components (CMAC) have been increasingly used in recent years. However, the iliac fixed flange of CMAC is still a mechanically weak area, where nonuniform stress distribution and micromotion may cause prosthesis failure. This study aimed to enhance the iliac fixation effect by enhancing the structure of the iliac flange or using a quadri-flange CMAC. The biomechanical performance was compared to provide a theoretical basis for clinical application.

Methods: The inhomogeneous finite element analysis (FEA) model was reconstructed according to the Paprosky IIIB acetabular defect. The biomechanical performance of enhanced triflanged and quadri-flange CMAC was evaluated according to the peak stress and the Von Mises stress distribution under routine conditions. The relative micromotion between the pelvis and prosthesis was analyzed to assess the stability of the implant.

Results: The peak stresses of the enhanced triflanged and quadri-flange CMAC were 126.90 and 140.70 MPa under gait cycle, respectively. The stress distribution in the enhanced triflanged CMAC was more uniform. In contrast, nonuniform stress distribution and larger high-stress concentration regions were found in the quadri-flange CMAC, especially in the screw contact sites between the screw and superolateral bone of the ilium. The results of micromotion showed that there was a larger proportion of units with > 28 μm in the quadri-flange CMAC (15%), while the enhanced triflanged CMAC structure had a smaller ratio (8%).

Conclusion: The enhanced triflanged CMAC has better stress, stress distribution, and micromotion than quadri-flange CMAC in this model. In cases where both prostheses are suitable for use, the enhanced triflanged CMAC is more highly recommended.

Aims: Meniscal degeneration may precede or indicate early-stage osteoarthritis (OA); however, the pathogenetic involvement of the NF-κB pathway and its upstream IκB kinase (IKK) is unclear. This study investigated the functional role of IKK in the pathogenesis of meniscal degeneration, and the efficacy of IKKε inhibition as a therapeutic approach.

Methods: IKK expression in normal and OA human menisci was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed in human meniscal cells. Additionally, meniscal degeneration was induced in wild-type mice and treated with intra-articular injection of the IKKε/TBK1 inhibitors amlexanox and BAY-985 every five days for four weeks. Meniscal degeneration was also induced in IKKε knockout mice. Mice were subsequently examined histologically.

Results: IKK protein expression was increased in human OA menisci. In vitro, the expression of meniscal degeneration-related factors was decreased after knockdown of each IKK, particularly IKKε, using small interfering RNA in human OA meniscal cells. Conversely, IKKε overexpression significantly increased the expression of these factors, and amlexanox and BAY-985 cancelled this effect. Western blot analysis showed that IKKε overexpression increased IκBα and p65 (RELA) phosphorylation. In vivo, both IKKε deletion and intra-articular injection of IKKε/TBK1 inhibitors protected mouse menisci against degeneration.

Conclusion: These results indicate that IKKs are involved in meniscal degeneration when it constitutes the preliminary or early stage of OA, with IKKε possibly playing a significant role. Furthermore, IKKε regulates meniscal degeneration through NF-κB signalling-mediated catabolism. Two IKKε/TBK1 inhibitors, amlexanox and BAY-985, are potential targets for the treatment of meniscal degeneration prior to OA.

Aims: Osteoporotic vertebral fractures substantially contribute to disability and often require surgical intervention. However, some challenges, such as implant failure and suboptimal bone regeneration, limit current treatments. Adipose-derived stem cells are promising for regenerative therapy because they are easily obtained, highly proliferative, and resistant to osteoporosis-related symptoms. This study aimed to evaluate the combined effects of osteogenic adipose-derived stem cell spheroids and β-tricalcium phosphate on vertebral bone regeneration in a rat osteoporotic vertebral fracture model.

Methods: Osteoporosis was induced in 33 rats (11 per group) by ovariectomy, and defects were created in the L4 and L5 vertebrae. Adipose-derived stem cells were spheroidized and mixed with β-tricalcium phosphate scaffolds. Groups included osteogenic spheroids, undifferentiated spheroids, and β-tricalcium phosphate alone. Bone regeneration was assessed using micro-CT, histology, and biomechanical testing at four and eight weeks. Further in vitro analyses were conducted.

Results: The osteogenic spheroid group showed significantly higher bone mass, fusion score, and mechanical strength than the control group did. Histological analysis revealed enhanced new bone formation and β-tricalcium phosphate integration. Gene expression analysis revealed osteogenic marker (alkaline phosphatase (ALP), osteocalcin (OCN), and runt-related transcription factor 2 (Runx2)) and regenerative factor (bone morphogenetic protein 7 (BMP-7), insulin-like growth factor 1 (IGF-1), hepatocyte growth factor 1 (HGF-1), and octamer-binding transcription factor4 (Oct4) upregulation, along with reduced apoptosis. Further, adipose-derived stem cell survival was confirmed at the repair site. These results indicate that adipose-derived stem cells contribute to both paracrine and direct osteogenesis.

Conclusion: Combining osteogenic adipose-derived stem cell spheroids with β-tricalcium phosphate scaffolds effectively promotes vertebral bone regeneration in osteoporotic vertebral fracture. This approach is a promising strategy for improving osteoporotic fracture repair with potential clinical applications.

Aims: This study aimed to explore the genotype and phenotype correlation of patients with multiple osteochondroma (MO), and validate phenotypic differences in ATDC5 cell model with EXT1 or EXT2 gene disruption (EXT1^-/- or EXT2^-/-).

Methods: Mutation analysis was employed in 27 families with MO using polymerase chain reaction (PCR)-Sanger sequencing and targeted next-generation sequencing (t-NGS). ATDC5 cell model with EXT1^-/- or EXT2^-/- was established using CRISPR/Cas9 technology. Markers of chondrocyte proliferation and differentiation were assessed through quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and dyeing experiments at different timepoints.

Results: A total of 27 pathogenic mutations were identified in EXT1 and EXT2 genes, in which nine were novel mutations. In terms of mutation rate, onset age, medical treatment age, and numbers of moderate/severe (II/III) patients, the numbers with EXT1 gene mutations were more than those with EXT2 gene mutations. ATDC5 cell model with EXT1^-/- or EXT2^-/- was successfully established. The proliferation rate of ATDC5 chondrocytes in mutant groups (EXT1^-/- and EXT2^-/-) was higher than in WT group. The expressions of proliferation markers, including α-1 chain of type II collagen (COL2A1), aggrecan (ACAN), and SRY-box transcription factor 9 (SOX9), were almost all higher in mutant groups than that in WT group. Moreover, the expression of differentiation indicators, including α-1 chain of type X collagen (COL10A1), Runt-related transcription factor 2 (RUNX2), and matrix metallopeptidase 13 (MMP13), was increased in mutant groups compared to WT group. The Alcian blue and Alizarin red staining obtained similar results.

Conclusion: Clinical research identified nine novel mutations in EXT1 and EXT2 genes from 27 families with MO, and patients with EXT1 mutations have more severe symptoms than with EXT2 mutations. Cellular experiments suggested that EXT1 and EXT2 gene mutations promote proliferation and differentiation of chondrocytes, which were consistent with clinical research.

Aims: As global ageing and life expectancy increase, the prevalence and incidence of osteoarthritis (OA) are expected to rise. Transcutaneous carbon dioxide (CO₂) therapy has been shown to promote muscle regeneration, fracture healing, strengthen athletic endurance, and aid recovery from peripheral nerve damage and cancer. However, its effect on symptom modification and inflammation in OA is largely unknown. This study aimed to examine whether CO₂ therapy could slow the progression of OA and relieve OA-related inflammation in a chemically or surgically induced model in rats.

Methods: OA model was induced in 32 nine-week-old male Wistar rats by intra-articular injection of monosodium iodoacetate (MIA) and surgically induced by destabilization of the medial meniscus (DMM) in the knee joint. The pathogenesis period of MIA was set at two weeks, and for DMM at four weeks. After the creation of the OA model, either CO₂ therapy or sham intervention was applied daily for 20 minutes, and treatment was applied at two weeks. Behavioural assessments were completed at the end of the intervention period, and then knee joints were harvested. Non-demineralized frozen sections were prepared, and samples were examined histologically.

Results: Assessments of knee joint diameter showed that knee swelling in the DMM model improved significantly after two weeks of CO₂ therapy compared to the control group. The histomorphometric evaluation showed a significant increase in chondrocyte density in the CO₂ group compared to the MIA and DMM groups. Furthermore, the number of matrix metalloproteinase 13 (MMP13), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), and proinflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 positive cells decreased in the CO₂ group. In contrast, the number of aggrecan and type II collagen-positive cells increased.

Conclusion: Our results demonstrate that transcutaneous CO₂ therapy improves OA-related inflammation and suppresses the degeneration of articular cartilage.