Pyroptosis in Osteoarthritis: Molecular Mechanisms and Therapeutic Implications.

Osteoarthritis (OA) is a chronic disease that causes pain and functional impairment by affecting joint tissue. Its global impact is noteworthy, causing significant economic losses and property damage. Despite extensive research, the underlying pathogenesis of OA remain an area of ongoing investigation. It has recently been discovered that the OA progression is significantly influenced by pyroptosis. Pyroptosis is a complex process that involves three pathways culminating in the assembly of Gasdermin-D (GSDMD)-N-terminal (GSDMD-NT) into pores through aggregation on the plasma membrane. The aggregation of GSDMD-NT proteins stimulates the release of inflammatory mediators, such as Interleukin-1ß (IL-1ß), Interleukin-18 (IL-18), and Matrix Metallopeptidase 13 (MMP13), ultimately leading to cellular lysis. The pyroptosis process in specific cells, including synovial macrophages, fibroblast-like synoviocytes (FLS), chondrocytes, and subchondral osteoblasts, contributs factor to the development of OA. Currently, the specific cells that undergo pyroptosis first are not yet fully understood, and it remains unknown whether pyroptosis in one cell can trigger the same process in other cells. Therefore, targeting pyroptosis could potentially offer a novel treatment approach for OA patients. We present a comprehensive analysis of the molecular mechanisms and key features of pyroptosis. We also outline the current research progress on various aspects, including synovial tissue, articular cartilage, extracellular matrix (ECM), and subchondral bone, with a focus on pyroptosis. The aim is to provide theoretical references for the effective management of OA.

Complete resorption of the humerus in metastatic thyroid carcinoma: a case report.

BACKGROUND: Thyroid carcinoma is the most common endocrinological malignancy, but its spread to bone is rare. Particularly, bone metastases leading to complete resorption of the humerus are extremely uncommon. We aimed to explore factors affecting treatment decision in humeral metastasis by presenting a case and analyze the possible treatments via conducting a literature review. CASE PRESENTATION: We described a case of a 68-year-old woman experiencing chronic pain in her right upper arm for six years. Clinical, radiological, and pathological evaluations confirmed humeral metastasis from thyroid carcinoma. Surgical treatments like tumor removal or limb amputation were suggested for prolonging life and pain relief, but the patient refused them and pursued conservative managements such as herbal medicine, radioactive iodine (131I) therapy, and Levothyroxine Sodium(L-T4). The humeral destruction aggravated gradually, ultimately leading to complete resorption of her right humerus. The patient could not move her right shoulder, but her forearm motion was almost normal; thus, she could complete most of her daily living activities independently. Surgical treatments such as limb amputation were advised but she still refused them for preservation of the residual limb function and preferred conservative managements. CONCLUSION: A personalized multidisciplinary approach is important for patients with bone metastasis. The balance between limb amputation for life-prolonging and pain relief and limb salvage for preservation of residual function and social and psychological well-being should be considered. Our literature review revealed that some novel surgical treatments and techniques are available for bone metastases. This case adds to our current understanding of bone metastases and will contribute to future research and treatments.

Risk of metabolic abnormalities in osteoarthritis: a new perspective to understand its pathological mechanisms.

Although aging has traditionally been viewed as the most important risk factor for osteoarthritis (OA), an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA, particularly in younger individuals. Metabolic abnormalities, such as obesity and type II diabetes, are strongly linked to OA, and they affect both weight-bearing and non-weight-bearing joints, thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight. This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk, including the impact of abnormal glucose and lipid metabolism, the potential pathogenesis and targeted therapeutic strategies.

Multiple cullin-associated E3 ligases regulate cyclin D1 protein stability.

Cyclin D1 is a key regulator of cell cycle progression, which forms a complex with CDK4/6 to regulate G1/S transition during cell cycle progression. Cyclin D1 has been recognized as an oncogene since it was upregulated in several different types of cancers. It is known that the post-translational regulation of cyclin D1 is controlled by ubiquitination/proteasome degradation system in a phosphorylation-dependent manner. Several cullin-associated F-box E3 ligases have been shown to regulate cyclin D1 degradation; however, it is not known if additional cullin-associated E3 ligases participate in the regulation of cyclin D1 protein stability. In this study, we have screened an siRNA library containing siRNAs specific for 154 ligase subunits, including F-box, SOCS, BTB-containing proteins, and DDB proteins. We found that multiple cullin-associated E3 ligases regulate cyclin D1 activity, including Keap1, DDB2, and WSB2. We found that these E3 ligases interact with cyclin D1, regulate cyclin D1 ubiquitination and proteasome degradation in a phosphorylation-dependent manner. These E3 ligases also control cell cycle progression and cell proliferation through regulation of cyclin D1 protein stability. Our study provides novel insights into the regulatory mechanisms of cyclin D1 protein stability and function.

Cartilage organoids and osteoarthritis research: a narrative review.

Osteoarthritis (OA) is one of the most common degenerative joint diseases, significantly impacting individuals and society. With the acceleration of global aging, the incidence of OA is increasing. The pathogenesis of osteoarthritis is not fully understood, and there is no effective way to alleviate the progression of osteoarthritis. Therefore, it is necessary to develop new disease models and seek new treatments for OA. Cartilage organoids are three-dimensional tissue masses that can simulate organ structure and physiological function and play an important role in disease modeling, drug screening, and regenerative medicine. This review will briefly analyze the research progress of OA, focusing on the construction and current development of cartilage organoids, and then describe the application of cartilage organoids in OA modeling, drug screening, and regeneration and repair of cartilage and bone defects. Finally, some challenges and prospects in the development of cartilaginous organoids are discussed.

miR-204 ameliorates osteoarthritis pain by inhibiting SP1-LRP1 signaling and blocking neuro-cartilage interaction.

Osteoarthritis (OA) is a painful degenerative joint disease and is the leading cause of chronic disability among elderly individuals. To improve the quality of life for patients with OA, the primary goal for OA treatment is to relieve the pain. During OA progression, nerve ingrowth was observed in synovial tissue and articular cartilage. These abnormal neonatal nerves act as nociceptors to detect OA pain signals. The molecular mechanisms for transmitting OA pain in the joint tissues to the central nerve system (CNS) is currently unknown. MicroRNA miR-204 has been demonstrated to maintain the homeostasis of joint tissues and have chondro-protective effect on OA pathogenesis. However, the role of miR-204 in OA pain has not been determined. In this study, we investigated interactions between chondrocytes and neural cells and evaluated the effect and mechanism of miR-204 delivered by exosome in the treatment of OA pain in an experimental OA mouse model. Our findings demonstrated that miR-204 could protect OA pain by inhibition of SP1- LDL Receptor Related Protein 1 (LRP1) signaling and blocking neuro-cartilage interaction in the joint. Our studies defined novel molecular targets for the treatment of OA pain.