Mechanism of cuproptosis in the diagnosis and treatment of orthopedic-related diseases

Abstract

BACKGROUND: Studies have shown that cuproptosis plays a critical role in the pathogenesis and treatment of orthopedic diseases. However, the regulatory roles and mechanisms of cuproptosis in orthopedic-related diseases remain unclear. OBJECTIVE: To review the roles and mechanisms of cuproptosis in orthopedic-related diseases. METHODS: A literature search was conducted in the PubMed database using the following English keywords: "cuproptosis," "copper steady state," "osteoarthritis," "osteoporosis," "rheumatoid arthritis," "osteosarcoma," and "oxidative stress." The search included publications up to March 2025. According to the inclusion criteria, 55 articles were finally included for review. RESULTS AND CONCLUSION: In osteoarthritis, excessive copper ions induce the expression of metal-regulatory transcription factor 1, indirectly activating matrix metalloproteinases and leading to cartilage degradation. Cuproptosis disrupts the tricarboxylic acid cycle and inhibits glutamine metabolism, triggering oxidative stress and accelerating chondrocyte death. In osteoporosis, cuproptosis suppresses glutamine metabolism and mineralization in osteoblasts while promoting osteoclast differentiation, thereby disrupting the balance between bone formation and resorption. In rheumatoid arthritis, copper ions activate the phosphatidylinositol 3-kinase/protein kinase B/mitogen-activated protein kinase signaling pathway, promoting synovial cell abnormal activation and inflammatory factor release, exacerbating joint destruction. In osteosarcoma, high concentrations of copper ions selectively kill tumor cells by targeting ferredoxin 1, inducing mitochondrial dysfunction and proteotoxic stress. The mechanisms of cuproptosis in orthopedic diseases are complex and diverse, involving multiple cell types and signaling pathways. Targeting cuproptosis or its related pathways may provide new strategies for the treatment of orthopedic diseases, such as the application of copper chelators or copper ion carriers, which hold significant clinical potential. Future research should further explore the specific regulatory mechanisms of cuproptosis and its therapeutic value in disease treatment.

1. Introduction

Orthopedic-related diseases, such as osteoarthritis, osteoporosis, and rheumatoid arthritis, are common in the field of orthopedics, while osteosarcoma peaks in incidence during adolescence. These conditions affect the tissue, structure, and function of bones and joints, leading to high disability rates worldwide. The pathological mechanisms of these orthopedic diseases are complex and diverse, involving factors such as bone metabolic imbalance, inflammatory responses, oxidative stress, and cell death. With aging, bone tissue metabolism gradually declines, disrupting the balance of bone metabolism and ultimately leading to the occurrence of a series of orthopedic diseases [1]. Current treatments, including anti-inflammatory drugs, lifestyle modifications, and surgical interventions, can slow the progression of orthopedic diseases [2-3], but they cannot fundamentally reverse tissue damage or tumor progression due to obstacles such as cartilage repair and bone regeneration. Therefore, there is an urgent need to explore new therapeutic targets to overcome the difficulties in treating orthopedic diseases.

In recent years, the relationship between copper metabolism abnormalities and skeletal diseases has become a research hotspot. Early studies mainly focused on the direct effects of copper ion concentration on bone metabolism. However, the proposal of cuproptosis in 2022 has opened a new perspective in this field. Cuproptosis is a novel copper-dependent programmed cell death modality. Unlike previously known cell death pathways, cuproptosis involves the tricarboxylic acid cycle and oxidative stress [4]. Copper ions bind to lipoylated proteins in the tricarboxylic acid cycle (such as ferredoxin 1), inducing mitochondrial dysfunction and proteotoxic stress, ultimately leading to cell death. This discovery not only enriches the theoretical framework of cell death but also provides new ideas for the treatment of orthopedic diseases.

Studies have shown that cuproptosis is associated with orthopedic diseases, and there is a complex relationship between them. Maintaining copper homeostasis is crucial for bone health [5], and cuproptosis plays an important role in the pathogenesis of orthopedic diseases such as osteoarthritis, osteoporosis, and rheumatoid arthritis. In these diseases, cuproptosis affects chondrocytes, osteoclasts, osteoblasts, and synovial cells, contributing to the development and progression of orthopedic conditions. Targeting cuproptosis may delay the progression of these diseases. This review mainly discusses the roles and mechanisms of cuproptosis in orthopedic-related diseases, aiming to provide new insights for the diagnosis and treatment of these conditions.