Subchondral osteoclasts and osteoarthritis: new insights and potential therapeutic avenues.

Osteoarthritis (OA) is the most common joint disease, and good therapeutic results are often difficult to obtain due to its complex pathogenesis and diverse causative factors. After decades of research and exploration of OA, it has been progressively found that subchondral bone is essential for its pathogenesis, and pathological changes in subchondral bone can be observed even before cartilage lesions develop. Osteoclasts, the main cells regulating bone resorption, play a crucial role in the pathogenesis of subchondral bone. Subchondral osteoclasts regulate the homeostasis of subchondral bone through the secretion of degradative enzymes, immunomodulation, and cell signaling pathways. In OA, osteoclasts are overactivated by autophagy, ncRNAs, and Rankl/Rank/OPG signaling pathways. Excessive bone resorption disrupts the balance of bone remodeling, leading to increased subchondral bone loss, decreased bone mineral density and consequent structural damage to articular cartilage and joint pain. With increased understanding of bone biology and targeted therapies, researchers have found that the activity and function of subchondral osteoclasts are affected by multiple pathways. In this review, we summarize the roles and mechanisms of subchondral osteoclasts in OA, enumerate the latest advances in subchondral osteoclast-targeted therapy for OA, and look forward to the future trends of subchondral osteoclast-targeted therapies in clinical applications to fill the gaps in the current knowledge of OA treatment and to develop new therapeutic strategies.

Redox signaling and antioxidant defense in osteoclasts.

Bone remodeling is essential for the repair and replacement of damaged or aging bones. Continuous remodeling is necessary to prevent the accumulation of bone damage and to maintain bone strength and calcium balance. As bones age, the coupling mechanism between bone formation and absorption becomes dysregulated, and bone loss becomes dominant. Bone development and repair rely on interaction and communication between osteoclasts and surrounding cells. Osteoclasts are specialized cells that are accountable for bone resorption and degradation, and any abnormalities in their activity can result in notable alterations in bone structure and worsen disease symptoms. Recent findings from transgenic mouse models and bone analysis have greatly enhanced our understanding of the origin, differentiation pathway, and activation stages of osteoclasts. In this review, we explore osteoclasts and discuss the cellular and molecular events that drive their generation, focusing on intracellular oxidative and antioxidant signaling. This knowledge can help develop targeted therapies for diseases associated with osteoclast activation.

Byakangelicol suppresses TiPs-stimulated osteoclastogenesis and bone destruction via COX-2/NF-κB signaling pathway.

Aseptic loosening (AL) is considered a significant cause of prosthesis revision after arthroplasty and a crucial factor in the longevity of an artificial joint prosthesis. The development of AL is primarily attributed to a series of biological reactions, such as peri-prosthetic osteolysis (PPO) induced by wear particles around the prosthesis. Chronic inflammation of the peri-prosthetic border tissue and hyperactivation of osteoclasts are key factors in this process, which are induced by metallic wear particles like Ti particles (TiPs). In our in vitro study, we observed that TiPs significantly enhanced the expression of inflammation-related genes, including COX-2, IL-1ß and IL-6. Through screening a traditional Chinese medicine database, we identified byakangelicol, a traditional Chinese medicine molecule that targets COX-2. Our results demonstrated that byakangelicol effectively inhibited TiPs-stimulated osteoclast activation. Mechanistically, we found that byakangelicol suppressed the expression of COX-2 and related pro-inflammatory factors by modulating macrophage polarization status and NF-κB signaling pathway. The in vivo results also demonstrated that byakangelicol effectively inhibited the expression of inflammation-related factors, thereby significantly alleviating TiPs-induced cranial osteolysis. These findings suggested that byakangelicol could potentially be a promising therapeutic approach for preventing PPO.

What do osteoporosis and osteoarthritis have in common? An integrated study of overlapping differentially expressed genes in bone mesenchymal stem cells of osteoporosis and osteoarthritis.

OBJECTIVE: For identification of aberrantly expressed genes in mesenchymal stem cells of osteoporosis (OP) and osteoarthritis (OA), Gene Expression Omnibus (GEO) datasets were integrated to investigate the intersection point. METHODS: GSE35958 (osteoporosis) and GSE19664 (osteoarthritis) datasets were obtained from GEO database. The abnormally expressed genes were analyzed by GEO2R. Functional enrichment was explored by Metascape database and R software. The String database and Cytoscape software were used to build the protein-protein interaction network and identify hub genes. GSE35957 and GSE116925 were used as verification datasets. Single-cell analysis and pseudotime analysis were undertaken. CTDbase, Network Analyst, HPA database, HERB database and MIRW database were used to research the information, tissue and cell distribution, regulation, interaction and ingredients targeting the hub genes. Additionally, in vitro experiments such as RT-PCR, ALP staining and immunofluorescence were undertaken as verification tests. RESULTS: Ten hub genes were identified in this study. All these genes play an important role in bone or cartilage generation. They have diagnostic values and therapeutic potential for OA and OP. Single-cell analysis visualized the cell distribution and pseudotime distribution of these genes. Some potential therapeutic ingredients of these genes were identified, such as curcumin, wogonin and glycerin. In vitro experiments, RT-PCR results showed that COL9A3 and MMP3 were downregulated and PTH1R was upregulated during osteogenic induction of BMSC. Immunohistochemical results showed the expression trend of MMP3 and COL2A1. CONCLUSION: Ten abnormal hub genes of osteoporosis and osteoarthritis were identified successfully by this study. They were important regulatory genes for healthy bone and cartilage. These genes could be the common connections between osteoporosis and osteoarthritis as well as treatment targets. Further study of the regulatory mechanism and treatment effects of these genes would be valuable. The results of this study could contribute to further research.

CB2 regulates oxidative stress and osteoclastogenesis through NOX1-dependent signaling pathway in titanium particle-induced osteolysis.

Periprosthetic osteolysis (PPO) induced by wear particles at the interface between the prosthesis and bone is a crucial issue of periprosthetic bone loss and implant failure. After wear and tear, granular material accumulates around the joint prosthesis, causing a chronic inflammatory response, progressive osteoclast activation and eventual loosening of the prosthesis. Although many studies have been conducted to address bone loss after joint replacement surgeries, they have not fully addressed these issues. Focusing on osteoclast activation induced by particles has important theoretical implications. Cannabinoid type II receptor (CB2) is a seven-transmembrane receptor that is predominantly distributed in the human immune system and has been revealed to be highly expressed in bone-associated cells. Previous studies have shown that modulation of CB2 has a positive effect on bone metabolism. However, the exact mechanism has not yet been elucidated. In our experiments, we found that NOX1-mediated ROS accumulation was involved in titanium particle-stimulated osteoclast differentiation. Furthermore, we confirmed that CB2 blockade alleviated titanium particle-stimulated osteoclast activation by inhibiting the NOX1-mediated oxidative stress pathway. In animal experiments, downregulation of CB2 alleviated the occurrence of titanium particle-induced cranial osteolysis by inhibiting osteoclasts and scavenging intracellular ROS. Collectively, our results suggest that CB2 blockade may be an attractive and promising therapeutic scheme for particle-stimulated osteoclast differentiation and preventing PPO.

The Emerging Role of the Mitochondrial Respiratory Chain in Skeletal Aging.

Maintenance of mitochondrial homeostasis is crucial for ensuring healthy mitochondria and normal cellular function. This process is primarily responsible for regulating processes that include mitochondrial OXPHOS, which generates ATP, as well as mitochondrial oxidative stress, apoptosis, calcium homeostasis, and mitophagy. Bone mesenchymal stem cells express factors that aid in bone formation and vascular growth. Positive regulation of hematopoietic stem cells in the bone marrow affects the differentiation of osteoclasts. Furthermore, the metabolic regulation of cells that play fundamental roles in various regions of the bone, as well as interactions within the bone microenvironment, actively participates in regulating bone integrity and aging. The maintenance of cellular homeostasis is dependent on the regulation of intracellular organelles, thus understanding the impact of mitochondrial functional changes on overall bone metabolism is crucially important. Recent studies have revealed that mitochondrial homeostasis can lead to morphological and functional abnormalities in senescent cells, particularly in the context of bone diseases. Mitochondrial dysfunction in skeletal diseases results in abnormal metabolism of bone-associated cells and a secondary dysregulated microenvironment within bone tissue. This imbalance in the oxidative system and immune disruption in the bone microenvironment ultimately leads to bone dysplasia. In this review, we examine the latest developments in mitochondrial respiratory chain regulation and its impacts on maintenance of bone health. Specifically, we explored whether enhancing mitochondrial function can reduce the occurrence of bone cell deterioration and improve bone metabolism. These findings offer prospects for developing bone remodeling biology strategies to treat age-related degenerative diseases.

Identification and validation of ferroptosis key genes in bone mesenchymal stromal cells of primary osteoporosis based on bioinformatics analysis.

Primary osteoporosis has long been underdiagnosed and undertreated. Currently, ferroptosis may be a promising research direction in the prevention and treatment of primary osteoporosis. However, the specific mechanism of ferroptosis in primary osteoporosis remains a mystery. Differentially expressed genes (DEGs) were identified in bone mesenchymal stromal cells (BMSCs) of primary osteoporosis and heathy patients from the GEO databases with the help of bioinformatics analysis. Then, we intersected these DEGs with the ferroptosis dataset and obtained 80 Ferr-DEGs. Several bioinformatics algorithms (PCA, RLE, Limma, BC, MCC, etc.) were adopted to integrate the results. Additionally, we explored the potential functional roles of the Ferr-DEGs via GO and KEGG. Protein-protein interactions (PPI) were used to predict potential interactive networks. Finally, 80 Ferr-DEGs and 5 key Ferr-DEGs were calculated. The 5 key Ferr-DEGs were further verified in the OVX mouse model. In conclusion, through a variety of bioinformatics methods, our research successfully identified 5 key Ferr-DEGs associated with primary osteoporosis and ferroptosis, namely, sirtuin 1(SIRT1), heat shock protein family A (Hsp70) member 5 (HSPA5), mechanistic target of rapamycin kinase (MTOR), hypoxia inducible factor 1 subunit alpha (HIF1A) and beclin 1 (BECN1), which were verified in an animal model.

The expression of heat shock protein A12B (HSPA12B) in non-Hodgkin's lymphomas.

BACKGROUND: Heat shock protein A12B (HSPA12B) plays a considerable protective role for cells, tissues, and organs against various noxious conditions. However, the expression of HSPA12B in cancer biology remains controversial. This study aimed to investigate the expression of HSPA12B and its role in cell adhesion mediated drug resistance (CAM-DR) of non-Hodgkin's lymphoma (NHL). METHODS: In this study, the expression of HSPA12B in NHL was determined by immunohistochemical, and the effect of HSPA12B expression on the prognosis of NHL was analyzed by Kaplan-Meier curves. Then, the transfection technique was used to research the effect of HSPA12B in cell apoptosis. The most important was to study the expression changes of HSPA12B in the adhesion model and the effect of overexpression of HSPA12B on CAM-DR. RESULTS: We analyzed the relationship between the expression levels of HSPA12B and clinical parameters in NHL. The expression of HSPA12B was directly related to the different NHL variants. We overexpressed HSPA12B in 2 NHL cell lines and found a subsequent reduction in apoptosis. More specifically, we used an adhesion assay to demonstrate that HSPA12B expression was induced in NHL cells when they adhered to fibronectin (FN) or bone marrow stroma cells (BMSCs). Finally, it was revealed that HSPA12B overexpression enhances CAM-DR. CONCLUSIONS: Our data suggest that HSPA12B may play a functional role in CAM-DR and is thus a potential novel target for NHL treatment.