An integrated network pharmacology, molecular docking and experiment validation study to investigate the potential mechanism of Isobavachalcone in the treatment of osteoarthritis.

BACKGROUND: In many different plants, including Dorstenia and Psoralea corylifolia L., Isobavachalcone (IBC) is a naturally occurring flavonoid chemical having a range of biological actions, including anti-inflammatory, immunomodulatory, and anti-bacterial. The "Theory of Medicinal Properties" of the Tang Dynasty states that Psoralea corylifolia L. has the ability to alleviate discomfort in the knees and waist. One of the most widespread chronic illnesses, osteoarthritis (OA), is characterized by stiffness and discomfort in the joints. However, there hasn't been much research done on the effectiveness and underlying processes of IBC in the treatment of osteoarthritis. AIM OF THE STUDY: To investigate the potential efficacy and mechanism of IBC in treating osteoarthritis, we adopted an integrated strategy of network pharmacology, molecular docking and experiment assessment. MATERIALS AND METHODS: The purpose of this research was to determine the impact of IBC on OA and the underlying mechanisms. IBC and OA possible targets and processes were predicted using network pharmacology, including the relationship between IBC and OA intersection targets, Cytoscape protein-protein interaction (PPI) to obtain key potential targets, and GO and KEGG pathway enrichment analysis to reveal the probable mechanism of IBC on OA. Following that, in vitro tests were carried out to confirm the expected underlying processes. Finally, in vivo tests clarified IBC's therapeutic efficacy on OA. RESULTS: We anticipated and validated that the impact of IBC on osteoarthritis is mostly controlled by the PI3K-AKT-NF-κB signaling pathway by combining the findings of network pharmacology analysis, molecular docking and Experiment Validation. CONCLUSIONS: This study reveals the IBC has potential to delay OA development.

H3K36 methyltransferase NSD1 protects against osteoarthritis through regulating chondrocyte differentiation and cartilage homeostasis.

Osteoarthritis (OA) is one of the most common joint diseases, there are no effective disease-modifying drugs, and the pathological mechanisms of OA need further investigation. Here, we show that H3K36 methylations were decreased in senescent chondrocytes and age-related osteoarthritic cartilage. Prrx1-Cre inducible H3.3K36M transgenic mice showed articular cartilage destruction and osteophyte formation. Conditional knockout Nsd1Prrx1-Cre mice, but not Nsd2Prrx1-Cre or Setd2Prrx1-Cre mice, replicated the phenotype of K36M/+; Prrx1-Cre mice. Immunostaining results showed decreased anabolic and increased catabolic activities in Nsd1Prrx1-Cre mice, along with decreased chondrogenic differentiation. Transcriptome and ChIP-seq data revealed that Osr2 was a key factor affected by Nsd1. Intra-articular delivery of Osr2 adenovirus effectively improved the homeostasis of articular cartilage in Nsd1Prrx1-Cre mice. In human osteoarthritic cartilages, both mRNA and protein levels of NSD1 and OSR2 were decreased. Our results indicate that NSD1-induced H3K36 methylations and OSR2 expression play important roles in articular cartilage homeostasis and OA. Targeting H3K36 methylation and OSR2 would be a novel strategy for OA treatment.

Femoral neck fracture after femoral head necrosis: a case report and review of the literature.

INTRODUCTION: Pathological fractures of the femoral neck caused by necrosis of the femoral head are extremely rare. Here, we report a rare case of bilateral femoral head osteonecrosis extending to the femoral neck, with bilateral pathological fractures of the femoral neck occurring within a short period of time. CASE REPORT: A 65-year-old male with a 25-year history of daily consumption of 750 ml of liquor, presented with right hip pain after labor for 1 month. He subsequently sustained a right femoral neck fracture without trauma and underwent a right total hip arthroplasty. Two months later, he suffered a non-traumatic left femoral neck fracture and underwent a left total hip arthroplasty. Histopathological examination revealed osteonecrosis of the femoral head and neck, along with the presence of osteoclasts and granulomatous inflammation. Bone mineral density testing also showed osteoporosis. The bilateral femoral neck fractures were ruled out to be caused by any other pathological factors. DISCUSSION: This is the first report of pathological fractures of the bilateral femoral neck caused by femoral head necrosis. During the literature review process, we found that this case conforms to the histological characteristics of rapidly destructive hip disease and analyzed the etiology of femoral head necrosis and the pathogenesis of femoral neck fractures.

A nomogram for predicting the risk of new vertebral compression fracture after percutaneous kyphoplasty.

BACKGROUND: New vertebral compression fractures (NVCFs) are common adverse events in percutaneous kyphoplasty (PKP). The present study aimed to investigate the risk factors for NVCFs in patients after PKP and to construct a nomogram for the prediction of the risk of re-fracture. METHODS: We retrospectively analyzed the medical records of patients after PKP surgery between January 2017 and December 2020. Patients were divided into an NVCF group (n = 225) and a control group (n = 94) based on the presence or absence of NVCFs, respectively, at follow-up within 2 years after surgery. Lasso regression was used to screen for risk factors for re-fracture. Based on the results, a Lasso-logistic regression model was developed, and its prediction performance was evaluated using receiver operating characteristic curves, calibration, and decision curve analysis. The model was visualized, and a nomogram was constructed. RESULTS: A total of eight potential predictors were obtained from Lasso screening. Advanced age, low body mass index, low bone mineral density, lack of anti-osteoporosis treatment, low preoperative vertebral body height, vertebral body height recovery ≥ 2, cement leakage, and shape D (lack of simultaneous contact of bone cement with the upper and lower plates) were included in the logistic regression model. CONCLUSIONS: A nomogram for predicting postoperative NVCF in PKP was developed and validated. This model can be used for rational assessment of the magnitude of the risk of developing NVCFs after PKP, and can help orthopedic surgeons make clinical decisions aimed at reducing the occurrence of NVCFs.

Cerium Oxide Nanoparticles Promote Osteoplastic Precursor Differentiation by Activating the Wnt Pathway.

Osteoplastic precursors are critical for fracture repair and bone homeostasis maintenance. Cerium oxide nanoparticles (CeO2 NPs) can promote the osteogenic differentiation of mesenchymal stem cells and secrete vascular endothelial growth factors. However, little is known about its role in precursor osteoblasts; therefore, we further investigated the effect and mechanism of CeO2 NPs in precursor osteoblasts. Cell counting kit-8 analysis was utilized to detect the toxicity of CeO2 NPs on MC3T3-E1 mouse osteogenic precursor cells. Then, alizarin red S staining was employed to assess the degree of extracellular matrix mineralization, and quantitative real-time polymerase chain reaction analysis was performed to measure the levels of osteogenesis-related genes. To identify differentially expressed genes, mRNA-sequencing was performed. Subsequently, GO and KEGG analyses were deployed to identify the major downstream pathways, whereas Western blot was used for verification. CeO2 NPs significantly enhanced the ability of MC3T3-E1 precursor osteoblasts to enhance matrix mineralization and increased the expression of osteogenic genes such as runt-related transcription factor 2, collagen Iα1, and osteocalcin. Pathway analysis revealed that CeO2 NPs enhanced the nuclear translocation of ß-catenin and activated the Wnt pathway by promoting family with sequence similarity 53 member B/simplet expression, while Western blot analysis indicated the same results. After using a Wnt pathway inhibitor (KYA1797K), the simulative effect of CeO2 NPs was abolished. This study revealed that CeO2 NPs promoted MC3T3-E1 precursor osteoblast differentiation by activating the Wnt pathway.

All-Inside Anterior Cruciate Ligament Reconstruction Using an Anterior Half of the Peroneus Longus Tendon Autograft.

BACKGROUND: The peroneus longus tendon (PLT) has been used as a graft in many orthopaedic surgical procedures because of its comparable biomechanical strength with the native anterior cruciate ligament (ACL). Despite its potential, few studies have been performed to investigate the clinical reliability of ACL reconstruction using a PLT autograft. PURPOSE: To assess the clinical outcomes and donor-site morbidity of ACL reconstruction using an anterior half of the PLT (AHPLT) autograft in patients with an isolated ACL injury. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between January 2016 and January 2017, a total of 21 patients with an isolated ACL injury underwent all-inside single-bundle ACL reconstruction using an AHPLT autograft. Knee stability was assessed using the Lachman test, pivot-shift test, and KT-2000 arthrometer (side-to-side difference) with 134-N anterior force and at 30° of knee flexion. Knee function was evaluated using the International Knee Documentation Committee score, Lysholm score, and Tegner score. Donor-site morbidity was assessed using ankle eversion and plantarflexion strength as well as the American Orthopaedic Foot & Ankle Society scoring system and the Foot and Ankle Disability Index. RESULTS: At a mean final follow-up of 40.1 months (range, 36-48 months), the KT-2000 arthrometer side-to-side difference was significantly lower compared with preoperatively (1.1 ± 0.62 vs 7.0 ± 2.18 mm, respectively; P < .001). The mean preoperative International Knee Documentation Committee, Lysholm, and Tegner scores were 52.0 ± 8.27, 50.9 ± 8.50, and 1.8 ± 0.87, respectively, increasing significantly to 94.2 ± 2.61, 95.2 ± 2.64, and 6.8 ± 1.50, respectively, at final follow-up (P < .001 for all). All patients had grade 5 muscle strength in ankle eversion and plantarflexion at the donor site, with mean American Orthopaedic Foot & Ankle Society and Foot and Ankle Disability Index scores of 96.8 and 97.6, respectively. No complications or reoperations occurred. CONCLUSION: All-inside ACL reconstruction using an AHPLT autograft produced good functional scores and stability without obvious ankle-site morbidity.

Distinct expression trend of signature antigens of Staphylococcus aureus osteomyelitis correlated with clinical outcomes.

The major limitations of clinical outcome predictions of osteomyelitis mediated by Staphylococcus aureus (S. aureus) are not specific and definitive. To this end, current studies aim to investigate host immune responses of trend changes of the iron-regulated surface determinant (Isd) of IsdA, IsdB, IsdH, cell wall-modifying proteins of amidase (Amd) and glucosaminidase (Gmd), and secreted virulence factor of chemotaxis inhibitory protein S. aureus (CHIPS) and staphylococcal complement inhibitor (SCIN) longitudinally to discover their correlationship with clinical outcomes. A total of 55 patients with confirmed S. aureus infection of the long bone by clinical and laboratory methods were recruited for the study. Whole blood was collected at 0, 6, 12 months for the serum that was used to test IsdA, IsdB, IsdH, Gmd, Amd, CHIPS, and SCIN using a customized Luminex assay after clinical standard care parameters were collected. The patients were then divided into two groups: (1) infection controlled versus (2) adverse outcome based on clinical criteria for statistical analysis. We found that standard clinical parameters were unable to distinguish therapeutic outcomes. Significant overexpression of all antigens was confirmed in infection patients at 0-, 6-, and 12-month time points. A distinct expression trend and dynamic changes of IsdB, Amd, Gmd, and CHIPS were observed between infection controlled and adverse outcome patients, while the IsdA, IsdH, SCIN remained demonstrated no statistical significance. We conclude that dynamic changes of specific antigens could predict clinical outcomes of S. aureus osteomyelitis. Clinical Relevance: The trend changes of host immune responses to S. aureus specific antigens of IsdB, Gmd, Amd, and CHIPS could predict clinical outcomes of S. aureus osteomyelitis.

Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification.

Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk+Scx+ TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling.

A Novel EXT1 Mutation Identified in a Family with Multiple Osteochondromas.

AIMS: Multiple exostoses (MO), also referred to as hereditary multiple exostoses (HME), is an autosomal dominant inherited skeletal disorder that has been found to be associated with mutations in the EXT1 and EXT2 genes. In the present study, we report a Chinese family with HME and our mutational analyses of the EXT1 and EXT2 genes in affected and unaffected individuals. METHODS: All exons of the EXT1 and EXT2 genes in seven family members were polymerase chain reaction amplified from blood and sequenced. RESULTS: A heterozygous mutation (c.1056G>T) was identified in exon 2 of the EXT1 gene in the proband and other affected family members; this mutation was not found in the unaffected family members. DISCUSSION: This c.1056G>T mutation is located in the exostosin domain of the EXT1 protein and leads to an amino acid change of Glutamine (Gln) to Histidine (His) at position 352. Homology searches reveal that Gln352 is highly conserved in many species and may play an essential role in the normal function of the EXT1 protein. CONCLUSIONS: This study contributes to a better understanding of the genetic basis of HME, expands the known mutational spectrum of EXT1, and provides a reference for genetic counseling and prenatal diagnosis of this family.

A novel EXT2 frameshift mutation identified in a family with multiple osteochondromas.

Multiple osteochondromas (MO) is an autosomal inherited disease that is characterized by benign bone tumors. However, the underlying mechanism of MO at a molecular level requires further investigation. The majority of mutations associated with MO occur in the exostosin glycosyltransferase genes (EXT)1 or EXT2. In the present study, the genetic causes of the disease were investigated. Polymerase chain reaction amplification, followed by DNA sequencing of the complete EXT1 and EXT2 coding regions, were conducted in a family with MO (n=5). A novel frameshift mutation in exon 3 of EXT2 (c.660delG) was detected. The production of a defective EXT2 protein, lacking 450 C-terminal amino acid residues is predicted to be caused by the c.660delG mutation, located within the exostosin domain of EXT2. The missing residues contain the exostosin and glycosyltransferase family 64 domains, which are critical for the function of EXT2. The novel c.660delG frameshift mutation in the EXT2 gene extends the etiological understanding of MO and may provide an effective reference for genetic counseling and prenatal diagnosis in this family.

Novel exostosin-2 mutation identified in a Chinese family with hereditary multiple osteochondroma.

Hereditary multiple osteochondroma (HMO) is an autosomal dominant genetic disorder characterized by multiple outgrowing bony tumors capped by cartilage, generally affecting the metaphyses. The disease is known as hereditary multiple exostoses, familial exostosis, multiple cartilaginous exostoses or hereditary malformation of cartilage. The prevalence of HMO in Europe and the Unites States is ~1:100,000, although it has not been reported in China. The disease is often accompanied by pain, asymmetry and skeletal malformations, including forearm and leg bending deformities, limb length discrepancies, and knee internal and external rotation abnormalities. Mutations to exostosin-1 (EXT1) and EXT2 mutations cause insufficient heparan sulfate biosynthesis, leading to chondrocyte proliferation, abnormal bone growth in neighboring regions, multiple exostoses, and ultimately malignant transformation. The risk of malignant degeneration to osteochondrosarcoma increases with age, despite the low lifetime risk (~1%). The present study selected a clinical feature of typical HMO pedigrees, and examined mutations in family members by Sanger sequencing. Each of the five patients examined had a novel heterozygous nonsense mutation, c.67C>T p.Arg23*. The mutation is located prior to the EXT2 exostosin domains in the amino acid sequence and results in a protein truncation of the 705 C-terminal amino acids. The present study provides molecular genetic evidence for a novel causal mechanism of HMO, and provides the basis for clinical genetic counseling for similar diseases.

Multiple large xanthomas: A case report.

A 23-year-old male patient presented with multiple large masses in his elbows, buttocks, knees, Achilles tendons, feet, shoulders and hands. The large masses in the elbows and buttocks measured ~6×5×5 cm and ~7×5×4 cm, respectively. The patient presented with an elevated level of low-density lipoprotein cholesterol, and had been previously diagnosed with homozygous familial hypercholesterolemia (FH) and multiple xanthomas. Local surgical excisions were performed to remove the massive xanthomas from the elbows and buttocks, and histological analysis of the surgical specimens confirmed the previous diagnosis of homozygous FH (HoFH). The aim of the present study was to report a rare case of HoFH coinciding with multiple, large and widely-distributed xanthomas and to discuss the clinical characteristics, in order to provide a better understanding of xanthomas and FH.

Identification of a rare case of intra-articular osteochondroma manifesting as three loose bodies in a patient with hereditary multiple osteochondromas: A case report.

Hereditary multiple osteochondromas (HMO) is an autosomal dominant bone disorder characterised by the presence of multiple benign cartilage-capped tumours. Exostosin-1 (EXT1) and EXT2 are the major morbigenous genes associated with HMO, mutations in which are responsible for 90% of all HMO cases. In patients with HMO, osteochondromas arise adjacent to the metaphysis and typically remain in the metaphyseal region of the long bones. Therefore, it is rare for osteochondromas to be identified intra-articularly, although they may manifest as loose bodies. The present study describes a rare case of HMO manifesting as limited flexing range in the right knee joint of a 27-year-old male patient. Computed tomography and magnetic resonance imaging (MRI) revealed three intra-articular osteochondromas located in the intercondylar fossa of the patient's right knee. The intra-articular osteochondromas and protuberant extra-articular osteochondromas around the right knee were resected, resulting in improved right knee function and no postoperative recurrence. Pathological analysis revealed that the intra-articular osteochondromas had a thinner cartilage cap layer than the extra-articular osteochondromas. In addition, genetic analysis of the patient and the patient's mother was conducted. From this, it was determined that a nonsense mutation, c.115G>T (p.E39X) in exon 1 of the EXT1 gene, was the cause of HMO in this case. Thus, it is proposed that osteochondromas with a pedicle within the knee, may tear and become loose intra-articular bodies, resulting in limited joint function and thereby contributing to the progression of HMO.

[Case-control study on superior labrum from anterior to posterior repair and biceps tenodesis for the treatment of type II SLAP injury].

OBJECTIVE: To compare clinical outcomes of superior labrum from anterior to posterior (SLAP) repair and biceps tenodesis in treating type I SLAP injury. METHODS: From March 2009 to March 2012, 38 patients with type II SLAP injury were treated with SLAP repair and biceps tenodesis, and all patients were unilateral SLAP injury. Sixteen patients treated with biceps tenodesis included 8 males and 7 females with an average age of (49.3±3.7) years old (ranged, 45 to 54); 10 cases were on the left side and 6 cases on the right side; 10 cases were caused by falling down, 2 cases were caused by throwing damage and 4 cases were caused by daily life damage; the time from injury to operation were from 3 to 8 weeks. Twenty-two patients treated with SLAP repair included 14 males and 8 females with an average age of (49.0±2.8) years old (ranged, 44 to 56); 13 cases were on the left side and 9 cases were on the right side; 14 cases were caused by falling down, 5 cases were caused by throwing damage and 3 cases were caused by daily life damage; the time from injury to operation were from 3 to 7 weeks. Preoperative, postoperative at 6 months, 1 year and 2 years' UCLA and SST score were compared between two groups. RESULTS: There was no significant differences in UCLA and SST score between two groups before operation. At 6 months after operation, UCLA and SST score in biceps tenodesis group was higher than SLAP group, and action,range of anteflexion, strength of anteflexion, degree of satisfaction in biceps tenodesis group was higher than SLAP group. There was no significant meaning in SST and UCLA score between two groups at 1 and 2 years after operation. CONCLUSION: Short-term efficacy of biceps tenodesis for SLAP injury is better than SLAP repair, but long-term efficacy is fairly.

Novel EXT1 mutation identified in a pedigree with hereditary multiple exostoses.

Hereditary multiple exostoses (HME) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors. EXT1 located on chromosome 8q23-q24 and EXT2 located on 11p11-p12 are the main disease-causing genes which are responsible for ~90% of HME cases. Mutations of EXT1 or EXT2 result in insufficient heparan sulfate biosynthesis, which facilitates chondrocyte proliferation, boosts abnormal bone growth of neighboring regions, causes multiple exostoses, and ultimately leads to possible malignant transformation. A family who displayed typical features of HME was enrolled in the present study. Mutation screening by Sanger sequencing identified a novel heterozygous nonsense mutation c.1902C>A (p.Tyr634X) in the EXT1 gene exclusively in all 3 patients, which is located in the glycosyltransferase domain and results in the truncation of 112 amino acids at the C-terminus of the EXT1 protein. Thus, the present study identified a novel disease-causing EXT1 mutation in a pedigree with HME, which provides additional evidence for developing quick and accurate genetic tools for HME diagnosis.