From cartilage degeneration to pain sensitization: a multi-tissue mitochondrial dysfunction network in osteoarthritis
- 1Ganzhou Hospital-Nanfang Hospital, Southern Medical University (Ganzhou People’s Hospital), Ganzhou, Jiangxi Province, China
- 2The First Affiliated Hospital, Jiangxi Medical College,Nanchang University, Nanchang, Jiangxi Province, China
Abstract
Osteoarthritis (OA) is one of the most common degenerative joint diseases, and its clinical burden arises not only from degenerative changes and synovial inflammation but is also closely associated with chronic pain, functional impairment, and reduced quality of life. In patients with OA, imaging-detected structural damage and pain severity are not always consistent, suggesting that symptom persistence may also be driven by mechanisms such as metabolic disturbance, inflammatory amplification, and neural sensitization. Existing evidence indicates that mitochondrial abnormalities can be observed in cartilage, synovium, subchondral bone, and sensory nerve-related compartments, but the strength of evidence and the causal hierarchy differ across compartments. In chondrocytes, disruption of mitochondrial homeostasis is often accompanied by imbalanced energy metabolism, oxidative stress, impaired quality control, and mtDNA damage, and is associated with cell aging, regulated cell death, and matrix degeneration. Mitochondrial stress in other joint and neural compartments may participate in local inflammation, abnormal bone remodeling, and peripheral and central pain sensitization. Mitochondria-derived DAMPs, and inflammatory mediators may mediate cross-compartment interactions, but current evidence is insufficient to establish a continuous causal chain from cartilage degeneration unidirectionally to pain sensitization. Therefore, mitochondria in OA are more appropriately regarded as a pathological network shared across multiple tissue compartments and potentially interacting with one another. Building on this perspective, this article takes pain sensitization as an important dimension for understanding structural damage and symptoms in OA, and uses the “metabolism-senescence-pain axis” as a hypothesis-generating framework to review the role of mitochondrial dysfunction in OA structural degeneration, cell aging, regulated cell death, and pain sensitization, with emphasis on distinguishing evidence across cartilage, synovium, subchondral bone, sensory neurons, and central nervous system-related compartments, and to discuss potential cross-compartment interactions mediated by DAMPs, and neuroimmune signaling. Furthermore, by integrating human, animal, in vitro, and translational studies, the existing evidence is stratified, and the progress and translational barriers of mitochondria-directed and related therapeutic strategies are summarized. Finally, this article proposes future directions such as cell type-specific delivery, mitochondrial biomarkers, candidate pain mechanism phenotypes, and composite “mechanism-symptom-structure” endpoints, thereby offering a foundation for dissecting mechanistic heterogeneity, patient stratification, and precision intervention in OA.
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BibTeX
@article{yang2026from,
title = {{From cartilage degeneration to pain sensitization: a multi-tissue mitochondrial dysfunction network in osteoarthritis}},
author = {Kanghua Yang and Kanghua Yang and Lin Li and Hui Yu},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1914283},
url = {https://doi.org/10.3389/fcell.2026.1914283},
note = {CC BY},
}
RIS
TY - JOUR
TI - From cartilage degeneration to pain sensitization: a multi-tissue mitochondrial dysfunction network in osteoarthritis
AU - Kanghua Yang
AU - Kanghua Yang
AU - Lin Li
AU - Hui Yu
PY - 2026
DA - 2026/10/23
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1914283
UR - https://doi.org/10.3389/fcell.2026.1914283
AB - Osteoarthritis (OA) is one of the most common degenerative joint diseases, and its clinical burden arises not only from degenerative changes and synovial inflammation but is also closely associated with chronic pain, functional impairment, and reduced quality of life. In patients with OA, imaging-detected structural damage and pain severity are not always consistent, suggesting that symptom persistence may also be driven by mechanisms such as metabolic disturbance, inflammatory amplification, and neural sensitization. Existing evidence indicates that mitochondrial abnormalities can be observed in cartilage, synovium, subchondral bone, and sensory nerve-related compartments, but the strength of evidence and the causal hierarchy differ across compartments. In chondrocytes, disruption of mitochondrial homeostasis is often accompanied by imbalanced energy metabolism, oxidative stress, impaired quality control, and mtDNA damage, and is associated with cell aging, regulated cell death, and matrix degeneration. Mitochondrial stress in other joint and neural compartments may participate in local inflammation, abnormal bone remodeling, and peripheral and central pain sensitization. Mitochondria-derived DAMPs, and inflammatory mediators may mediate cross-compartment interactions, but current evidence is insufficient to establish a continuous causal chain from cartilage degeneration unidirectionally to pain sensitization. Therefore, mitochondria in OA are more appropriately regarded as a pathological network shared across multiple tissue compartments and potentially interacting with one another. Building on this perspective, this article takes pain sensitization as an important dimension for understanding structural damage and symptoms in OA, and uses the “metabolism-senescence-pain axis” as a hypothesis-generating framework to review the role of mitochondrial dysfunction in OA structural degeneration, cell aging, regulated cell death, and pain sensitization, with emphasis on distinguishing evidence across cartilage, synovium, subchondral bone, sensory neurons, and central nervous system-related compartments, and to discuss potential cross-compartment interactions mediated by DAMPs, and neuroimmune signaling. Furthermore, by integrating human, animal, in vitro, and translational studies, the existing evidence is stratified, and the progress and translational barriers of mitochondria-directed and related therapeutic strategies are summarized. Finally, this article proposes future directions such as cell type-specific delivery, mitochondrial biomarkers, candidate pain mechanism phenotypes, and composite “mechanism-symptom-structure” endpoints, thereby offering a foundation for dissecting mechanistic heterogeneity, patient stratification, and precision intervention in OA.
SN - 2296-634X
ER -