The Repair Manual of a Fruit Fly Brain.

Osteoarthritis (OA) is a disease that affects the entire joint, characterized by primary pathological features such as degeneration of articular cartilage, subchondral bone remodeling, synovial inflammation, and osteophyte formation. The pathogenesis of OA involves complex interactions between abnormal mechanical loading and immune-inflammatory responses. Recent studies indicate that osteoarthritis is not simply a ‘wear-and-tear’ condition; rather, it is an immune-related disease primarily defined by persistent, low-grade chronic inflammation and abnormal activation of innate immune signaling pathways (, ). OA predominantly involves weight-bearing joints or those with high mobility, such as the hands, knees, and hips. Clinically, the main symptoms include joint pain, swelling, morning stiffness, and bony overgrowth. In advanced stages, joint deformities may arise, leading to significant impairment of joint function. At the microscopic level, OA is characterized by cartilage fissuring and erosion, synovitis, and abnormal bone formation (, ). Imaging and histopathological studies have demonstrated that synovitis is prevalent in OA. Magnetic resonance imaging (MRI) findings indicate that approximately 60% of OA patients exhibit synovial inflammation or hypertrophy. Furthermore, the severity of synovitis is significantly correlated with the progression of cartilage damage and the experience of joint pain (, ). The immune cells infiltrating the synovial tissue are predominantly macrophages, which account for approximately 65% of the total infiltrating cell population. The inflammatory cytokines released by M1-polarized macrophages—including TNF-α, IL-1β, and IL-6—establish a cytokine network that drives the degradation of the cartilage matrix (). The CCL2/CCR2 chemokine axis is crucial in mediating the directed recruitment of monocytes and macrophages to the synovium; its activation not only promotes the persistence of synovial inflammation but is also closely associated with the severity of OA pain (). Therefore, conducting a systematic immunological analysis of the pathogenesis of OA holds significant importance. Currently, OA is recognized as a leading cause of disability in China. Its prevalence and progression are correlated with factors such as age, gender, body weight, educational level, and socioeconomic status (). Research indicates that the incidence of OA is strongly associated with advancing age. With the acceleration of global aging trends, data released by the World Health Organization show that approximately 528 million people worldwide were affected by OA in 2019, about 73% of whom were aged 55 years or older (). According to a recent study published in , it is projected that nearly one billion individuals worldwide will be affected by OA by 2050 (). Cartilage is a highly differentiated tissue characterized by the absence of blood vessels, nerves, and lymphatic vessels (). Consequently, once damaged, it is challenging to regenerate. Currently, treatment options for OA remain limited, and there is no definitive method to cure affected patients (). The primary treatment approach consists of conservative measures, including anti-inflammatory and analgesic therapies, as well as chondroprotective therapy. When the disease progresses to an advanced stage, surgical interventions, such as joint replacement, are typically employed. However, the core objective of these treatment approaches primarily focuses on controlling pain and inflammatory responses (, ). Therefore, an in-depth analysis of the mechanisms underlying innate immune activation in OA, the regulation of synovial macrophage polarization, and the cascade amplification of inflammatory signaling networks is of great significance for identifying new immunological therapeutic targets. This article reviews recent advances in the study of the pathogenesis of OA, focusing on the integrative roles of signaling pathways and ion channels in the mechanostatic-inflammatory-immune transduction network, and discusses the limitations of current research and future directions, with the aim of providing guidance for immunological research on OA. The pathogenesis of (OA is highly intricate, primarily characterized by chondrocyte apoptosis and reduced cellular activity. These cellular behaviors are critically influenced by mechanical signals within the cellular microenvironment (). Current evidence suggests that multiple signaling pathways play regulatory roles in the progression of OA. Key pathways involved include the Hippo/Yes-associated protein (Hippo/YAP), Wnt/β-catenin, nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase (AMPK), cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathways. The following discussion will focus on the role of these six signaling pathways in the pathogenesis of OA, with the aim of