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.