Mitochondrial metabolic regulation of macrophage polarization in osteomyelitis and other orthopedic disorders: mechanisms and therapeutic opportunities

Abstract

Osteomyelitis is a complex infectious bone disease involving pathogen invasion, host immune responses, and dysregulation of the local microenvironment. As a critical component of the innate immune system, macrophages play a pivotal role in inflammatory responses and tissue repair. Their polarization states (M1/M2) directly influence disease progression, while mitochondrial metabolism, as the central hub of cellular energy metabolism, has recently been shown to play a key role in macrophage polarization and functional regulation. However, how mitochondrial metabolism regulates macrophage polarization to affect the pathological mechanisms of osteomyelitis, and how to develop novel therapeutic strategies based on this mechanism, remain critical scientific questions to be addressed. This review systematically summarizes the molecular mechanisms by which mitochondrial metabolism regulates macrophage polarization and its role in osteomyelitis, with a focus on the impact of mitochondrial dynamics (fission/fusion), metabolic reprogramming, and reactive oxygen species (ROS) generation on macrophage polarization. Additionally, potential therapeutic strategies targeting mitochondrial metabolism are analyzed. For the first time, this review integrates the interplay between mitochondrial metabolism and macrophage polarization in osteomyelitis, revealing how mitochondrial dysfunction exacerbates inflammation and bone destruction through metabolic reprogramming. Based on these findings, we propose novel therapeutic strategies targeting mitochondrial metabolism, offering new perspectives and directions for understanding the pathogenesis and clinical treatment of osteomyelitis.

Keywords: bone repair; inflammation; macrophage polarization; mitochondrial dynamics; mitochondrial metabolism; osteomyelitis.

FIGURE 1

Key Signaling Pathways Linking Mitochondrial Metabolism, Macrophage Polarization, and Osteomyelitis Progression. Under infectious and inflammatory conditions, M1 macrophages primarily rely on glycolysis. Enhanced glycolysis leads to succinate accumulation, which promotes ROS production and further amplifies glycolysis through positive feedback and stabilizes HIF-1α and NF-κB signaling. This stabilization induces the secretion of pro-inflammatory cytokines such as TNF-α and IL-6, activating osteoclasts and exacerbating bone resorption. Meanwhile, mTORC1 promotes the upregulation of glycolysis-related genes by activating HIF-1α, reinforcing the pro-inflammatory feedback loop, whereas AMPK inhibits mTORC1 activity via phosphorylation. IL-6 activates the JAK1-STAT3 axis to enhance M1 polarization, whereas IL-4 promotes M2 polarization through the JAK1-STAT6 axis. Additionally, the JAK1/STAT3/6 pathway suppresses NF-κB signaling. M2-type macrophages primarily rely on oxidative phosphorylation (OXPHOS) for their energy metabolism. Enhanced OXPHOS activity increases the activity of SIRT1, which in turn activates PGC-1α. PGC-1α further enhances OXPHOS activity and regulates PPARγ activity, thereby promoting the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β, ultimately facilitating osteogenesis and tissue repair. At the same time, Nrf2 activates the HO-1/GPX4 axis to reduce ROS levels and inhibit NF-κB signaling, thereby constraining M1 polarization, while simultaneously activating PPARγ to promote M2 polarization. These interconnected pathways orchestrate mitochondrial metabolism and macrophage polarization in osteomyelitis, ultimately dictating the balance between inflammatory bone destruction and reparative bone formation.

FIGURE 2

Macrophage Polarization and Pathological Progression in S.aureus-Induced Osteomyelitis. Upon Staphylococcus aureus invasion, macrophages engulf the pathogen, triggering Drp1-mediated mitochondrial fission and driving their polarization toward the pro-inflammatory M1 phenotype. As the infection progresses, upregulation of the fusion proteins Mfn1/2 shifts mitochondrial morphology from fragmented to fused, facilitating a transition to the reparative M2 phenotype. This M2 polarization promotes osteogenesis, dampens inflammation, and guides the lesion toward healing. However, biofilm formation encapsulates Staphylococcus aureus, enabling persistent bacterial survival and continuous toxin release. The result is necrotic bone, renewed mitochondrial fission, and heightened osteoclast activity. With bone resorption and formation occurring simultaneously, the lesion ultimately advances to chronic osteomyelitis.

FIGURE 3

Targeting mitochondrial metabolism for osteomyelitis Treatment. (A) Metabolic interventions for regulating Macrophage Polarization. (B) Nanomaterials and drug delivery Systems. (C) Combination therapy Strategies.