Angelicin Alleviates Post-Trauma Osteoarthritis Progression by Regulating Macrophage Polarization via STAT3 Signaling Pathway

Post-trauma osteoarthritis (PTOA) is the most common articular disease characterized by degeneration and destruction of articular cartilage (Bultink and Lems, Curr. Rheumatol Rep., 2013, 15, 328). Inflammatory response of local joint tissue induced by trauma is the most critical factor accelerating osteoarthritis (OA) progression (Sharma et al., 2019; Osteoarthritis. Cartilage, 28, 658–668). M1/M2 macrophages polarization and repolarization participates in local inflammation, which plays a major role in the progression of OA (Zhang et al., 2018; Ann. Rheum. Dis., 77, 1524–1534). The regulating effect of macrophage polarization has been reported as a potential therapy to alleviate OA progression. Synovitis induced by polarized macrophages could profoundly affect the chondrocyte and cartilage matrix (Zhang et al., 2018; Ann. Rheum. Dis., 77, 1524–1534). Generally, anti-inflammatory medications widely used in clinical practice have serious side effects. Therefore, we focus on exploring a new therapeutic strategy with fewer side effects to alleviate the synovitis. Angelicin (ANG) is traditional medicine used in various folk medicine. Previous studies have revealed that angelicin has an inhibitory effect on inflammation (Wei et al., 2016; Inflammation, 39, 1876–1882), tumor growth (Li et al., 2016; Oncology reports, 36, 3,504–3,512; Wang et al., 2017; Molecular Medicine Reports, 16, 5441–5449), DNA damage (Li et al., 2019; Exp. Ther. Med., 18, 1899–1906), and virus proliferation (Li et al., 2018; Front. Cell. Infect. Microbiol., 8, 178). But its specific effects on influencing the process of OA were rarely reported. In this study, the molecular mechanism of angelicin in vivo and in vitro was clearly investigated. Results showed that angelicin could regulate the M1/M2 ratio and function and alleviate the development of PTOA in the meanwhile. Bone marrow monocytes were isolated and induced by macrophage colony-stimulating factor (M-CSF), lipopolysaccharide (LPS) and interferon (IFN)-γ for M1 polarization and interleukin (IL)-4/IL-13 for M2 polarization. Subsequently, repolarization intervention was performed. The results indicate that angelicin can repolarize M1 toward M2 macrophages by upregulating the expression of CD9. Besides, angelicin can also protect and maintain M2 polarization in the presence of LPS/IFN-γ, and subsequently downregulate the expression of inflammatory mediators such as IL-1β and TNF-α. Mechanistically, angelicin can activate the p-STAT3/STAT3 pathway by conducting CD9/gp130 to repolarize toward M2 macrophages. These results suggest angelicin can alleviate the progression of OA by regulating M1/M2 polarization via the STAT3/p-STAT3 pathway. Therefore, angelicin may have a promising application and potential therapeutic value in OA clinical treatment

Progress in Aptamer-Mediated Drug Delivery Vehicles for Cancer Targeting and Its Implications in Addressing Chemotherapeutic Challenges

Aptamers are novel oligonucleotides with flexible three-dimensional configurations that recognize and bind to their cognate targets, including tumor surface receptors, in a high-affinity and highly specific manner. Because of their unique intrinsic properties, a variety of aptamer-mediated nanovehicles have been developed to directionally transport anti-cancer drugs to tumor sites to minimize systemic cytotoxicity and to enhance permeation by these tumoricidal agents. Despite advances in the selection and synthesis of aptamers and in the conjugation and self-assembly of nanotechnologies, current chemotherapy and drug delivery systems face great challenges. These challenges are due to the limitations of aptamers and vehicles and because of complicated tumor mechanisms, including heterogeneity, anti-cancer drug resistance, and hypoxia-induced aberrances. In this review, we will summarize current approaches utilizing tumor surface hallmarks and aptamers and their roles and mechanisms in therapeutic nanovehicles targeting tumors. Delivery forms include nanoparticles, nanotubes, nanogels, aptamer-drug conjugates, and novel molecular trains. Moreover, the obstacles posed by the aforementioned issues will be highlighted, and possible solutions will be acknowledged. Furthermore, future perspectives will be presented, including cutting-edge integration with RNA interference nanotechnology and personalized chemotherapy, which will facilitate innovative approaches to aptamer-based therapeutics

Scaffolding Biomaterials for Cartilage Regeneration

Completely repairing of damaged cartilage is a difficult procedure. In recent years, the use of tissue engineering approach in which scaffolds play a vital role to regenerate cartilage has become a new research field. Investigating the advances in biological cartilage scaffolds has been regarded as the main research direction and has great significance for the construction of artificial cartilage. Native biological materials and synthetic polymeric materials have their advantages and disadvantages. The disadvantages can be overcome through either physical modification or biochemical modification. Additionally, developing composite materials, biomimetic materials, and nanomaterials can make scaffolds acquire better biocompatibility and mechanical adaptability

Treatment of AO/OTA 31-A3 intertrochanteric femoral fractures with a percutaneous compression plate

OBJECTIVE: AO/OTA 31-A3 intertrochanteric femoral fractures have completely different fracture line directions and biomechanical characteristics compared with other types of intertrochanteric fractures. The choice of the fixation method has been a focus of dispute among orthopedic trauma surgeons. The purpose of this study was to review the outcomes of these fractures treated with a percutaneous compression plate at our institute. METHOD: Seventeen patients with AO/OTA 31-A3 intertrochanteric femoral fractures were treated with a percutaneous compression plate at our institute from January 2010 to December 2011. The clinical data and imaging results were retrospectively analyzed. RESULTS: The medical complication of popliteal vein thrombosis occurred in one patient. Sixteen patients were followed up for 12 to 21 months. Two patients had malunion and mild pain. Fracture collapse occurred in two patients, with one having head penetration. These two patients had moderate pain. There were no occurrences of nonunion or reoperation. The mean Harris hip score obtained during the last follow-up was 84.1 (61-97). Patients with a poor quality of reduction were more likely to have pain results (p = 0.001). A trend existed toward the presence of a poor quality of reduction (p = 0.05) in patients with a collapse of fracture. Patients with poor preoperative mobility were more likely to have a lower Harris hip score (p = 0.000). CONCLUSION: The percutaneous compression plate is an alternative device for the treatment of AO/OTA 31-A3 intertrochanteric femoral fractures. Good fracture reduction and an ideal placement position of the neck screw are important in the success of the device

The Signaling Pathways Involved in Chondrocyte Differentiation and Hypertrophic Differentiation

Chondrocytes communicate with each other mainly via diffusible signals rather than direct cell-to-cell contact. The chondrogenic differentiation of mesenchymal stem cells (MSCs) is well regulated by the interactions of varieties of growth factors, cytokines, and signaling molecules. A number of critical signaling molecules have been identified to regulate the differentiation of chondrocyte from mesenchymal progenitor cells to their terminal maturation of hypertrophic chondrocytes, including bone morphogenetic proteins (BMPs), SRY-related high-mobility group-box gene 9 (Sox9), parathyroid hormone-related peptide (PTHrP), Indian hedgehog (Ihh), fibroblast growth factor receptor 3 (FGFR3), and -catenin. Except for these molecules, other factors such as adenosine, O 2 tension, and reactive oxygen species (ROS) also have a vital role in cartilage formation and chondrocyte maturation. Here, we outlined the complex transcriptional network and the function of key factors in this network that determine and regulate the genetic program of chondrogenesis and chondrocyte differentiation

IL-8 Enhances Therapeutic Effects of BMSCs on Bone Regeneration via CXCR2-Mediated PI3k/Akt Signaling Pathway

Background/Aims: Tissue engineering bone transplantation with bone marrow mesenchymal stem cells (BMSCs) is an effective technology to treat massive bone loss, while molecular regulation of the bone regeneration processes remains poorly understood. Here, we aimed to assess the role of interleukin-8 (IL-8) in the recruitment of host cells by seeded BMSCs and in the bone regeneration. Methods: A transwell assay was performed to examine the role of IL-8/CXCR1/CXCR2/PI3k/Akt on the migration potential of hBMSCs. The in vitro chondrogenic differentiation of hBMSCs was assessed by examination of 2 chondrogenic markers, Sox9 and type 2 collagen (COL2). mBMSCs were used in tissue engineered bone (TEB) with/without IL-8 implanted into bone defect area with CXCR2 or Akt inhibitors. Density and Masson staining of the regenerated bone were assessed. The chondrogenesis was assessed by expression levels of associated proteins, Sox9 and COL2, by RT-qPCR and by immunohistochemistry. Results: IL-8 may trigger in vitro migration of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway. IL-8 enhances osteogenesis in the TEB-implanted bone defect in mice. IL-8 induces chondrogenic differentiation of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway in vitro and in vivo. Conclusions: IL-8 enhances therapeutic effects of MSCs on bone regeneration via CXCR2-mediated PI3k/Akt signaling pathway

MicroRNA-145 Regulates Chondrogenic Differentiation of Mesenchymal Stem Cells by Targeting Sox9

Chondrogenic differentiation of mesenchymal stem cells (MSCs) is accurately regulated by essential transcription factors and signaling cascades. However, the precise mechanisms involved in this process still remain to be defined. MicroRNAs (miRNAs) regulate various biological processes by binding target mRNA to attenuate protein synthesis. To investigate the mechanisms for miRNAs-mediated regulation of chondrogenic differentiation, we identified that miR-145 was decreased during transforming growth factor beta 3 (TGF-β3)-induced chondrogenic differentiation of murine MSCs. Subsequently, dual-luciferase reporter gene assay data demonstrated that miR-145 targets a putative binding site in the 3′-UTR of SRY-related high mobility group-Box gene 9 (Sox9) gene, the key transcription factor for chondrogenesis. In addition, over-expression of miR-145 decreased expression of Sox9 only at protein levels and miR-145 inhibition significantly elevated Sox9 protein levels. Furthermore, over-expression of miR-145 decreased mRNA levels for three chondrogenic marker genes, type II collagen (Col2a1), aggrecan (Agc1), cartilage oligomeric matrix protein (COMP), type IX collagen (Col9a2) and type XI collagen (Col11a1) in C3H10T1/2 cells induced by TGF-β3, whereas anti-miR-145 inhibitor increased the expression of these chondrogenic marker genes. Thus, our studies demonstrated that miR-145 is a key negative regulator of chondrogenic differentiation by directly targeting Sox9 at early stage of chondrogenic differentiation

The Signaling Pathways Involved in Chondrocyte Differentiation and Hypertrophic Differentiation

Chondrocytes communicate with each other mainly via diffusible signals rather than direct cell-to-cell contact. The chondrogenic differentiation of mesenchymal stem cells (MSCs) is well regulated by the interactions of varieties of growth factors, cytokines, and signaling molecules. A number of critical signaling molecules have been identified to regulate the differentiation of chondrocyte from mesenchymal progenitor cells to their terminal maturation of hypertrophic chondrocytes, including bone morphogenetic proteins (BMPs), SRY-related high-mobility group-box gene 9 (Sox9), parathyroid hormone-related peptide (PTHrP), Indian hedgehog (Ihh), fibroblast growth factor receptor 3 (FGFR3), and β-catenin. Except for these molecules, other factors such as adenosine, O2 tension, and reactive oxygen species (ROS) also have a vital role in cartilage formation and chondrocyte maturation. Here, we outlined the complex transcriptional network and the function of key factors in this network that determine and regulate the genetic program of chondrogenesis and chondrocyte differentiation

The application of human medical image-based finite element analysis in the construction of mouse osteoarthritis models

The anterior cruciate ligament plays an important role in maintaining the stability of the knee joint. Its injury is a common cause of articular cartilage degeneration and osteoarthritis (OA). The anterior cruciate ligament transection (ACLT) method is commonly employed to construct animal models for studying osteoarthritis pathogenesis. However, the precise mechanism of how anterior cruciate ligament injury leads to osteoarthritis is not fully understood. This study utilized finite element analysis (FEA) with human medical images to simulate the biomechanical characteristics of anterior cruciate ligament (ACL) injury. Osteoarthritis models were subsequently established in C57BL/6 mice using ACLT to explore the link between ACL injury and osteoarthritis development. The results of FEA showed that, after an anterior cruciate ligament injury, abnormal stress was concentrated in the medial and lateral of the femoral and tibial articular cartilage during knee flexion and extension. In order to better display the pathological changes of articular cartilage in the stress areas, the medial tibial cartilage was selected as a representative area to observe the continuous pathological changes of articular cartilage in ACLT-induced OA mice. The articular cartilage degeneration was most dramatic at four weeks post ACLT operation and then remained relatively stable. This study may have significant implications for the development of animal models of osteoarthritis and provide a reference for histopathological research on osteoarthritis