Strategies in product engineering of mesenchymal stem cell-derived exosomes: unveiling the mechanisms underpinning the promotive effects of mesenchymal stem cell-derived exosomes.

Articular cartilage injuries present a significant global challenge, particularly in the aging population. These injuries not only restrict movement due to primary damage but also exacerbate elderly degenerative lesions, leading to secondary cartilage injury and osteoarthritis. Addressing osteoarthritis and cartilage damage involves overcoming several technical challenges in biological treatment. The use of induced mesenchymal stem cells (iMSCs) with functional gene modifications emerges as a solution, providing a more stable and controllable source of Mesenchymal Stem Cells (MSCs) with reduced heterogeneity. Furthermore, In addition, this review encompasses strategies aimed at enhancing exosome efficacy, comprising the cultivation of MSCs in three-dimensional matrices, augmentation of functional constituents within MSC-derived exosomes, and modification of their surface characteristics. Finally, we delve into the mechanisms through which MSC-exosomes, sourced from diverse tissues, thwart osteoarthritis (OA) progression and facilitate cartilage repair. This review lays a foundational framework for engineering iMSC-exosomes treatment of patients suffering from osteoarthritis and articular cartilage injuries, highlighting cutting-edge research and potential therapeutic pathways.

Inlay structure can improve bone graft stability in the Bristow procedure.

BACKGROUND: Compared with the Latarjet procedure, the Bristow procedure has a lower screw-related complication rate but poor bone healing. A modified Inlay Bristow procedure has been reported to significantly improve the bone healing rate, but the biomechanical mechanism is unclear. The aim of this study was to evaluate the biomechanical stability of the bone graft between a modified Inlay Bristow procedure and the classic Bristow procedure. METHODS: Sixteen left scapula models (Sawbones, Composite Scapula, and fourth generation) were randomly divided into 2 groups (8:8). The bone graft in the first group was fixed with a 3.5 mm screw using the Inlay structure. The bone graft in the second group was fixed with a 3.5 mm screw via the traditional method. The maximum cyclic displacement, ultimate failure load and stiffness were evaluated biomechanically. The failure type was recorded for each model. RESULTS: Cyclic loading tests demonstrated that the maximum cyclic displacement of the Inlay procedure was significantly smaller (P = .001) than that of the classic procedure. The Inlay Bristow technique resulted in a significantly higher (P = .024) ultimate failure load than the classic Bristow technique. The stiffness of the classic group was 19.17 ± 4.01 N/mm and that of the inlay group was 22.34 ± 5.35 N/mm (P = .232). Failure was mainly due to bone graft fractures through the drill hole or glenoid bone fractures. CONCLUSION: Inlay Bristow fixation of the bone graft in a Sawbones model provides significantly stronger fixation and better time point zero stability than classic Bristow fixation, suggesting a higher likelihood of graft union.

Identification of heel bone mineral density as a risk factor of Alzheimer's disease by analyzing large-scale genome-wide association studies datasets.

Introduction: Both low bone mineral density (BMD) and Alzheimer's disease (AD) commonly co_occur in the older adult. Until now, the association between AD and BMD has been widely reported by observational studies. However, Mendelian randomization (MR) studies did not support the causal association between BMD and AD. We think that the lack of significant causal association between AD and BMD identified by recent MR studies may be caused by small number of potential instrumental variables. Methods: We conduct a MR study to evaluate the causal effect of heel BMD on the risk of AD using 1,362 genome-wide significant and independent (p < 5.00E-08) heel BMD genetic variants as the potential instrumental variables, which are identified by a large-scale genome wide association study (GWAS) of heel BMD in 394,929 UK Biobank individuals. Using these 1,362 genome-wide significant and independent heel BMD genetic variants, we extracted their corresponding AD GWAS summary results in IGAP AD GWAS dataset (n = 63,926) and FinnGen AD GWAS dataset (n = 377,277). Five methods including inverse-variance weighted meta-analysis (IVW), weighted median, MR-Egger, MR-PRESSO, and MRlap were selected to perform the MR analysis. 951 of these 1,362 genetic variants are available in AD GWAS dataset. Results: We observed statistically significant causal effect of heel BMD on the risk of AD using IVW in IGAP AD GWAS dataset (OR = 1.048, 95%CI: 1.002-1.095, p = 0.04) and FinnGen AD GWAS dataset (OR = 1.053, 95% CI:1.011-1.098, p = 0.011). Importantly, meta-analysis of IVW estimates from IGAP and FinnGen further supported the causal effect of heel BMD on the risk of AD (OR = 1.051, 95% CI: 1.02-1.083, p = 0.0013). Discussion: Collectively, our current MR study supports heel BMD to be a risk factor of AD by analyzing the large-scale heel BMD and AD GWAS datasets. The potential mechanisms underlying the association between heel BMD and AD should be further evaluated in future.

Introduction of an easy-to-operate arthroscopic test in detecting and treatment of meniscal instability: "suction drift" test.

OBJECTIVE: To explore the surgical guidance value of "suction drift" in osteoarticular meniscal instability. METHODS: The clinical data of 104 patients with significant knee symptoms following surgery were retrospectively analyzed. "Suction drift" was diagnosed in both groups. Depending on the treatment, patients treated with conventional debridement were assigned to group A, and those treated by meniscus suture until the disappearance of the "suction drift" phenomenon were included in group B. All patients were followed up for a minimum of 6 months after surgery. The postoperative Visual Analogue Scale (VAS) score, Lysholm knee score and the occurrence of meniscus-related symptoms were compared between the two groups. RESULTS: After puncture, 78 patients (75.0%) had excessive displacement of the meniscus, with 53 (67.9%) of them being followed-up for at least 6 months. Twenty-five patients in group A and twenty-eight in group B were included in the final analysis (The number of patients with "suction drift" in two groups was tested to be comparable, P>0.05). VAS score was significantly decreased and Lysholm knee score was markedly increased in both groups after treatment, with lower VAS score and higher Lysholm knee score in group B compared with group A. In addition, group A had a significantly higher incidence of meniscus-related symptoms (joint space tenderness, joint clicks, and noose sensation) than group B. CONCLUSIONS: "Suction drift" is a quick and easy-to-operate arthroscopic test, which can not only diagnose meniscus instability due to knee osteoarthrosis-induced meniscus degeneration, but also help determine the recovery of meniscus stability after suture, and significantly relieve symptoms.

Dulaglutide mitigates inflammatory response in fibroblast-like synoviocytes.

Rheumatoid arthritis is a common autoimmune disease primarily characterized by chronic inflammation, the formation of an invasive pannus, and destruction of the joints. In the present study, we employed real-time PCR and western blot analysis to investigate the role of dulaglutide in human fibroblast-like synoviocytes (FLS). The results of our study show that dulaglutide exerted a powerful protective effect by rescuing mitochondrial membrane potential, inhibiting the production of NOX-4, and abrogating TNF-α-induced downregulation of the antioxidant GSH. Our findings demonstrate that dulaglutide significantly ameliorated the expression of proinflammatory cytokines and chemokines including IL-1ß, IL-6, MCP-1, and HMGB-1. Matrix metalloproteinases mediate cartilage destruction, thereby aiding in pannus formation. Our findings indicate that dulaglutide treatment significantly downregulated the expression of MMP-3 and MMP-13, two crucial degradative enzymes. Importantly, the results of our study demonstrate that the beneficial effects of dulaglutide are mediated through the JNK/NF-κB signaling pathway, which has been suggested as a potential treatment target against RA. Taken together, the results of this study show that dulaglutide may exert significant protective effects against the progression of RA induced by TNF-α.

Arthroscopic subscapularis repair using single-row mattress suture technique: clinical results and structural integrity.

BACKGROUND: Rupture of the subscapularis (SSC) tendon, isolated or combined, is rare, and the treatment modalities are controversial. The purpose of this study was to evaluate, by magnetic resonance imaging (MRI), the clinical outcomes and structural integrity of the SSC tendon after all-arthroscopic repair with single-row mattress suture for isolated or combined SSC tendon tears. METHODS: This study included 68 patients who underwent all-arthroscopic repair using single-row mattress suture for isolated or combined SSC tendon tears between April 2011 and January 2013. The patients were evaluated by the visual analog scale for pain, American Shoulder and Elbow Surgeons score, Constant shoulder score, and SSC muscle strength measurement. MRI was used for assessment of the postoperative integrity of the SSC tendon. RESULTS: With a mean follow-up of 29.5 ± 4.0 months, the preoperative Constant shoulder and American Shoulder and Elbow Surgeons scores were 50.3 ± 21.0 and 46.6 ± 18.3, respectively, which improved at the last follow-up to 75.7 ± 16.6 and 81.3 ± 18.1, respectively, with statistical significance (P < .001). Belly-press and bear-hug test results showed some improvement in the last follow-up (>2 years) compared with the presurgical state (P = .125 and .650). A statistically significant SSC muscle strength deficit persisted in the postoperative state (P = .015). MRI evaluation showed a retear rate of 8.8%. CONCLUSIONS: Arthroscopic repair of isolated or combined SSC tears with the single-row mattress suture technique results in significant clinical improvements and enduring tendon integrity, although SSC strength remains reduced from that on the normal side.

MicroRNA-145 expression in the plasma of patients with benign and malignant bone tumors and its effects on osteosarcoma cell proliferation and migration.

BACKGROUND: The present study intends to investigate microRNA-145 expression level in the plasma and tissue of patients with benign and malignant bone tumors and its effects on the proliferation and migration of osteosarcoma cells. METHODS: Thirty-four cases of patients with bone tumors (malignant) and twenty cases with osteochondroma (benign) in the hospital were enrolled into the study. Meanwhile, thirty cases of healthy subjects admitted to the hospital for physical examination in the same period were selected as the control group. MicroRNA-145 expression levels in the plasma of patients in three groups were detected using real-time quantitative RT-PCR. The difference in microRNA-145 expression level in the tissue between patients with benign and malignant bone tumors were compared and analyzed. Human osteosarcoma cell line OS-732 was used for high and low expressions of microRNA-145. Its effect on osteosarcoma cell proliferation level was observed using CCK8 method, and its osteosarcoma cell invasion level was observed using Transwell method. RESULTS: MicroRNA-145 expression level in the plasma of patients with malignant bone tumors was significantly lower than that of patients with benign bone tumors; microRNA-145 expression level in the plasma of patients with benign bone tumors was significantly lower than that of healthy subjects; the differences were statistically significant (P<0.05). MicroRNA-145 expression level in the tissue of patients with malignant bone tumors was significantly lower than that of patients with benign bone tumors; the difference was statistically significant (P<0.05). Cell proliferation level of human osteosarcoma cell line OS-732 interfered with microRNA-145 was significantly increased, and its cell invasion capacity was also significantly increased; the differences were statistically significant (P < 0.05). However, cell proliferation level of OS-732 with microRNA-145 overexpression was significantly decreased, and OS-732 cell invasion capacity was also significantly decreased; the differences were statistically significant (P<0.05). CONCLUSIONS: Low expression of microRNA-145 in patients with malignant bone tumors may be involved in cell proliferation and invasion of malignant bone tumors like osteosarcoma as a tumor suppressor.

Anti-Citrullinated Protein Antibodies Induce Macrophage Subset Disequilibrium in RA Patients.

We used samples from rheumatoid arthritis (RA) patients to examine whether Anti-citrullinated protein antibodies (ACPAs) alter macrophage subset distribution and promote RA development. Macrophage subset distributions and interferon regulatory factor 4 (IRF4) and IRF5 expressions were analyzed. ACPAs were purified by affinity column. After RA and osteoarthritis (OA) patients' macrophages were cocultured with ACPAs, macrophage subsets and IRF4 and IRF5 expressions were measured. Small interfering RNAs (siRNAs) were transfected into ACPA-activated cells to suppress IRF4 or IRF5. Fluorescence-activated cell sorting (FACS), Western blot, and immunohistochemistry were performed. Macrophage subset disequilibrium occurred in RA patient synovial fluids. IRF4 and IRF5 were all expressed in the synovial fluid and synovium. ACPAs (40 IU/ml) could induce macrophages to polarize to M1 subsets, and the percentage of increased M1/M2 ratio of RA patients was higher than that of the OA patients. ACPAs also induce IRF4 and IRF5 protein expressions. IRF5 siRNA transfection impaired ACPA activity significantly. We demonstrated that macrophage subset disequilibrium occurred in RA patients. ACPAs induced IRF5 activity and led to M1 macrophage polarization.

Association of CCL13 levels in serum and synovial fluid with the radiographic severity of knee osteoarthritis.

OBJECTIVE: CCL13, a recently identified CC chemokine, plays an important role in the process of joint destruction, which is considered a common cause for osteoarthritis (OA). This study aims to examine the relation of CCL13 levels in serum and synovial fluid (SF) with the radiographic severity of OA. METHODS: CCL13 levels in serum and SF were evaluated using enzyme-linked immunosorbent assay method in 240 patients with knee OA and 134 control subjects. The progression of OA was classified using the Kellgren-Lawrence (KL) system by evaluating x-ray changes observed in anteroposterior knee radiography. RESULTS: Knee OA patients had higher levels of serum CCL13 compared with control subjects. Knee OA patients with KL grade 4 showed significantly elevated CCL13 levels in serum and SF compared with those with KL grades 2 and 3. Knee OA patients with KL grade 3 had significantly higher SF levels of CCL13 compared with those with KL grade 2. CCL13 levels in serum and SF of knee OA patients were significantly correlated with disease severity evaluated by KL grading criteria. CONCLUSIONS: CCL13 levels in serum and SF were correlated with the radiographic severity of OA. CCL13 levels in serum and SF may serve as a biomarker for the progression of OA.

Long-term survivorship analysis of hip arthroplasty with vitallium mold cup.

BACKGROUND: Cup arthroplasty was used in the initial attempts to preserve the bone stock of the femoral head and neck for hip reconstruction. However, little conclusive data are available regarding its long-term survivorship. METHODS: We present a long-term survivorship analysis (mean follow-up, 19.3 years; range, 5-36.6 years) after vitallium mold arthroplasty in 77 secondary osteoarthritic hips. RESULTS: Kaplan-Meier survivorship analysis predicted a survival rate for vitallium mold arthroplasty of 81.6% (95% confidence interval [CI], 76.7-86.5) at 20 years and 59.1% (95% CI, 51.8-66.5) at 30 years, with conversion to total hip arthroplasty as the endpoint. The mean Merle d'Aubigné and Postel hip score showed a significant decrease in mobility from 4.12 (range, 3.18-5.86) 6 months after the operation to 3.19 (range, 1.7-4.6) at the last follow-up. No significant differences were observed for the pain score from 6 months after the operation (5.05; range, 4.2-5.9) to the last follow-up (4.46; range, 2.88-6.04)) or score for the ability to walk, from 6 months after the operation (2.5; range, 1.4-3.6) to the last follow-up (3.13; range, 1.59-4.67). Radiographically, the proximal and medial migration of the cup measured at the last follow-up was 10.4 +/- 5.4 mm (P < 0.01) and 0.2 +/- 2.1 mm (P > 0.05), respectively. CONCLUSIONS: Our results indicate inferior long-term survivorship after vitallium mold compared with that after Charnley low-friction arthroplasty.

Osteochondroma in the lumbar intraspinal canal causing nerve root compression.

Osteochondromas, which are benign bone tumors that usually develop on long bones, tubular bones, are rarely found in the spine. If they are located in the spinal canal, they may cause nerve root or spinal cord compression, which is a rare but potentially catastrophic manifestation of osteochondromas. In this article, we report a case of a 38-year-old man who presented with low back pain, paresthesia, and weakness of the right lower extremity aggravating gradually for 5 months. No family history of this disease can be traced. The L4-L5 level computed tomography scan showed an abnormal bony protrusion arising from the right interior wall of L5 right lamina toward the intraspinal canal. The protrusion compressed the L5 nerve root severely. T2-weighted magnetic resonance imaging (MRI) of the same level revealed that the L5 nerve root and spinal dura mater were notably compressed by the intraspinal extradural exostosis attached to the right lamina of L5. Considering differential diagnosis, lumbar facet synovial cysts must be excluded as they can also cause myeloradiculopathy with the similar mechanism. The tumor, approximately 6x7x11 mm, was identified after laminectomy of the L5 laminae. Postoperative histopathologic examination confirmed our hypothesis of benign osteochondroma. Postoperatively, the patient recovered rapidly in neurological function and was free of symptoms. Surgery is essential to this rare case. Computed tomography and MRI are helpful for the preoperatively precise indication of tumor extent and its relationships with the adjacent.