Immature articular cartilage and subchondral bone covered by menisci are potentially susceptive to mechanical load

BACKGROUND: The differences of mechanical and histological properties between cartilage covered by menisci and uncovered by menisci may contribute to the osteoarthritis after meniscectomy and these differences are not fully understood. The purpose of this study is to investigate potential differences in the mechanical and histological properties, and in particular the collagen architecture, of the superficial cartilage layer and subchondral bone between regions covered and uncovered by menisci using immature knee. METHODS: Osteochondral plugs were obtained from porcine tibial cartilage that was either covered or uncovered by menisci. Investigation of the thickness, mechanical properties, histology, and water content of the cartilage as well as micro-computed tomography analysis of the subchondral bone was performed to compare these regions. Collagen architecture was also assessed by using scanning electron microscopy. RESULTS: Compared to the cartilage uncovered by menisci, that covered by menisci was thinner and showed a higher deformity to compression loading and higher water content. In the superficial layer of cartilage in the uncovered regions, collagen fibers showed high density, whereas they showed low density in covered regions. Furthermore, subchondral bone architecture varied between the 2 regions, and showed low bone density in covered regions. CONCLUSIONS: Cartilage covered by menisci differed from that uncovered in both its mechanical and histological properties, especially with regards to the density of the superficial collagen layer. These regional differences may be related to local mechanical environment in normal condition and indicate that cartilage covered by menisci is tightly guarded by menisci from extreme mechanical loading. Our results indicate that immature cartilage degeneration and subchondral microfracture may occur easily to extreme direct mechanical loading in covered region after meniscectomy

Culture temperature affects human chondrocyte messenger RNA expression in monolayer and pellet culture systems

Cell-based therapy has been explored for articular cartilage regeneration. Autologous chondrocyte implantation is a promising cell-based technique for repairing articular cartilage defects. However, there are several issues such as chondrocyte de-differentiation. While numerous studies have been designed to overcome some of these issues, only a few have focused on the thermal environment that can affect chondrocyte metabolism and phenotype. In this study, the effects of different culture temperatures on human chondrocyte metabolism- and phenotype-related gene expression were investigated in 2D and 3D environments. Human chondrocytes were cultured in a monolayer or in a pellet culture system at three different culture temperatures (32° C, 37° C, and 41° C) for 3 days. The results showed that the total RNA level, normalized to the threshold cycle value of internal reference genes, was higher at lower temperatures in both culture systems. Glyceraldehyde-3- phosphate dehydrogenase (GAPDH) and citrate synthase (CS), which are involved in glycolysis and the citric acid cycle, respectively, were expressed at similar levels at 32° C and 37° C in pellet cultures, but the levels were significantly lower at 41° C. Expression of the chondrogenic markers, collagen type IIA1 (COL2A1) and aggrecan (ACAN), was higher at 37° C than at 32° C and 41° C in both culture systems. However, this phenomenon did not coincide with SRY (sex-determining region Y)-box 9 (SOX9), which is a fundamental transcription factor for chondrogenesis, indicating that a SOX9-independent pathway might be involved in this phenomenon. In conclusion, the expression of chondrocyte metabolism-related genes at 32° C was maintained or enhanced compared to that at 37° C. However, chondrogenesis-related genes were further induced at 37° C in both culture systems. Therefore, manipulating the culture temperature may be an advantageous approach for regulating human chondrocyte metabolic activity and chondrogenesis

Contributions of biarticular myogenic components to the limitation of the range of motion after immobilization of rat knee joint

BACKGROUND: Muscle atrophy caused by immobilization in the shortened position is characterized by a decrease in the size or cross-sectional area (CSA) of myofibers and decreased muscle length. Few studies have addressed the relationship between limitation of the range of motion (ROM) and the changes in CSA specifically in biarticular muscles after atrophy because of immobilization. We aimed to determine the contribution of 2 distinct muscle groups, the biarticular muscles of the post thigh (PT) and those of the post leg (PL), to the limitation of ROM as well as changes in the myofiber CSAs after joint immobilization surgery. METHODS: Male Wistar rats (n = 40) were randomly divided into experimental and control groups. In the experimental group, the left knee was surgically immobilized by external fixation for 1, 2, 4, 8, or 16 weeks (n = 5 each) and sham surgery was performed on the right knee. The rats in the control groups (n = 3 per time point) did not undergo surgery. After the indicated immobilization periods, myotomy of the PT or PL biarticular muscles was performed and the ROM was measured. The hamstrings and gastrocnemius muscles from the animals operated for 1 or 16 weeks were subjected to morphological analysis. RESULTS: In immobilized knees, the relative contribution of the PT biarticular myogenic components to the total restriction reached 80% throughout the first 4 weeks and decreased thereafter. The relative contribution of the PL biarticular myogenic components remained <20% throughout the immobilization period. The ratio of the myofiber CSA of the immobilized to that of the sham-operated knees was significantly lower at 16 weeks after surgery than at 1 week after surgery only in the hamstrings. CONCLUSIONS: The relative contribution of the PT and PL components to myogenic contracture did not significantly change during the experimental period. However, the ratio of hamstrings CSAs to the sham side was larger than the ratio of medial gastrocnemius CSAs to the sham side after complete atrophy because of immobilization

Analysis of Molecular Changes and Features in Rat Knee Osteoarthritis Cartilage: Progress From Cellular Changes to Structural Damage

[Objective] Although knee osteoarthritis (KOA) is a common disease, there is a lack of specific prevention and early treatment methods. Hence, this study aimed to examine the molecular changes occurring at different stages of KOA to elucidate the dynamic nature of the disease. [Design] Using a low-force compression model and analyzing RNA sequencing data, we identified molecular changes in the transcriptome of knee joint cartilage, including gene expression and molecular pathways, between the cellular changes and structural damage stages of KOA progression. In addition, we validated hub genes using an external dataset. [Results] Gene set enrichment analysis (GSEA) identified the following pathways to be associated with KOA: “B-cell receptor signaling pathway, ” “cytokine-cytokine receptor interaction, ” and “hematopoietic cell lineage.” Expression analysis revealed 585 differentially expressed genes, with 579 downregulated and 6 upregulated genes. Enrichment and clustering analyses revealed that the main molecular clusters were involved in cell cycle regulation and immune responses. Furthermore, the hub genes Csf1r, Cxcr4, Cxcl12, and Ptprc were related to immune responses. [Conclusions] Our study provides insights into the dynamic nature of early-stage KOA and offers valuable information to support the development of effective intervention strategies to prevent the irreversible damage associated with KOA, thereby addressing a major clinical challenge

Deep Recurrent Factor Model: Interpretable Non-Linear and Time-Varying Multi-Factor Model

A linear multi-factor model is one of the most important tools in equity portfolio management. The linear multi-factor models are widely used because they can be easily interpreted. However, financial markets are not linear and their accuracy is limited. Recently, deep learning methods were proposed to predict stock return in terms of the multi-factor model. Although these methods perform quite well, they have significant disadvantages such as a lack of transparency and limitations in the interpretability of the prediction. It is thus difficult for institutional investors to use black-box-type machine learning techniques in actual investment practice because they should show accountability to their customers. Consequently, the solution we propose is based on LSTM with LRP. Specifically, we extend the linear multi-factor model to be non-linear and time-varying with LSTM. Then, we approximate and linearize the learned LSTM models by LRP. We call this LSTM+LRP model a deep recurrent factor model. Finally, we perform an empirical analysis of the Japanese stock market and show that our recurrent model has better predictive capability than the traditional linear model and fully-connected deep learning methods.Comment: In AAAI-19 Workshop on Network Interpretability for Deep Learnin

Attenuating Cartilage Degeneration in a Low Mechanical Compression Rat Model Through Intra-Articular Injections of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells

[Objective] Mechanical stimulation significantly contributes to posttraumatic osteoarthritis (PTOA), a condition that impedes patient recovery following intra-articular injury. Effective treatment options for compression-induced injuries are limited. Bone marrow-derived mesenchymal stem cell (BMSC) implantation has emerged as a potential therapeutic breakthrough for joint diseases. The aim of this study was to attenuate the progression of PTOA induced by cyclic loading and demonstrate the potential effectiveness of BMSCs in a rat model of low mechanical compression. [Design] Using a rat model of compression-induced articular cartilage injury, assessments were conducted 2, 4, and 8 weeks after cyclic compressive loading. The expression of matrix metallopeptidase 13, transforming growth factor-beta 3 (TGF-β3), insulin-like growth factor 1 (IGF-1), and cleaved caspase-3 was evaluated through immunohistochemistry to investigate the mechanistic aspects underlying the prevention of compression-induced injury following BMSCs treatment. [Results] Intra-articular injections of BMSCs significantly improved scores in the OARSI (Osteoarthritis Research Society International) Osteoarthritis Cartilage Histopathology Assessment System and Histological-Histochemical Grading System. This treatment showed positive outcomes in maintaining high relative cell density and reducing proteoglycan loss after cyclic compression-induced injury. The expression patterns of IGF-1 and TGF-β3 provide valuable insights into the presence and distribution of these growth factors in healthy and injured cartilage. [Conclusions] These findings highlight the efficacy of BMSCs treatment in attenuating the advancement of compression-induced injuries, albeit within a limited timeframe