Introduction
Osteoarthritis (OA) is the most common musculoskeletal disease among middle-aged and elderly people. With the increase in susceptible factors (such as aging and obesity) over time, the prevalence of OA has reached 7% [1]. Pain is the main clinical manifestation of OA, often accompanied by varying degrees of limited joint mobility, deformity, and peripheral muscle weakness [2]. Pain is mainly related to the infiltration of proinflammatory factors in the intra-articular environment. The posterior horn of the spinal cord releases inflammatory factors and pain-causing neurotransmitters, both of which in turn lead to increased neuronal excitability and aggravated pain [3, 4]. OA pain is positively associated with persistent knee synovitis, marked by recurrent effusion and bone marrow edema. This inflammatory condition, in turn, triggers the release of neurotransmitters by the central nervous system (CNS) [5]. Moreover, as the disease progresses, patients not only develop an increased pain sensitivity but also exhibit resistance to pain-relieving medications [6]. High-intensity interval training (HIIT), as a form of physical therapy, not only mitigates pain but also enhances the muscular support around the affected joints, leading to a delay in the progression of OA [7]. Nonetheless, it is imperative to elucidate the underlying mechanisms by which HIIT alleviates pain associated with OA, in order to provide robust evidence supporting the clinical implementation of HIIT in the management of OA.
Microglia, as glial cells, serve as crucial components of the innate immune system within the nervous tissues, acting as the primary line of defense in the CNS [8]. Neurotransmitter factors activate microglia in the CNS, manifesting as proliferation and migration, mainly divided into M1- and M2-type microglia. M1 microglia contribute to the release of pro-inflammatory factors, including TNF-α, IL-1β, and IL-6, leading to cellular death and tissue damage. Conversely, M2 microglia exhibit a neuroprotective role and releases anti-inflammatory factors, such as IL-10, IL-4, and TGF-β, which effectively inhibit neuroinflammation and promote tissue repair [9-11]. Recent studies have highlighted the pivotal role of promoting phenotypic shifts from M1 to M2 microglia as a key concept for alleviating chronic pain and exerting neuroprotective effects [12-14].
The Janus kinase 2 (Jak2)/ signal transducer and activator of transcription 3 (Stat3) pathway is involved in microglia activation and regulation of pain [15]. In addition, the Jak2/Stat3 pathway is also involved in various pathophysiological processes, such as inflammation regulation, and apoptosis, and has become a hotspot in the field of cytokine research [16]. When the Jak2/Stat3 pathway was inhibited, the inflammatory response mediated by microglia was attenuated and thus inflammatory pain would be alleviated [17]. Some studies have shown that exercise training can modulate the Jak2/Stat3 pathway. For example, in a rat model of myocardial infarction, exercise improved myocardial infarct size and fibrosis via Jak2/Stat3 [18]. In a mouse model of asthma, aerobic exercise participated in the regulation of airway inflammation through the Jak2/Stat3 signaling pathway, remodeling the effect of airway hyperresponsiveness [19]. Endurance exercise also increased the expression of Jak2 and Stat3 in the hypothalamus, thereby activating leptin signaling [20]. However, whether HIIT could promotes pheno-typic transformations of microglia through Jak2/Stat3 has not been elucidated.
Osteoarthritis (OA)-associated inflammatory responses are mediated not just by cartilage degeneration but also by the activation of microglia within the CNS, as an increasing body of evidence suggests [4, 21-23]. In our study, we developed an OA model to investigate whether HIIT could mitigate inflammation by inducing phenotypic shifts in microglia through the Jak2/Stat3 signaling pathway.