Inflammaging and immunosenescence-driven remodeling of the immune microenvironment in osteoarthritis: mechanisms, immune regulation and immune reprogramming
Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 141 references
TL;DR
It is highlighted that future OA treatment may gradually shift from symptom-oriented management toward disease-modifying therapy based on the identification of immune endotypes, and further studies are required to validate the underlying molecular mechanisms, evaluate safety, and conduct clinical trials, thereby facilitating the clinical translation of immune reprogramming strategies for OA.
Abstract
Osteoarthritis (OA) is a disorder of the whole-joint microenvironment involving mechanical loading, aging, metabolic stress, and dysregulated immune homeostasis. Within the OA joint microenvironment, senescent chondrocytes, synovial fibroblasts, and diverse immune cell populations contribute to a persistently amplified inflammatory network through the senescence-associated secretory phenotype (SASP), damage-associated molecular patterns (DAMPs), and signaling pathways mediated by metabolic reprogramming. In this context, inflammaging and immunosenescence are considered key mechanistic axes linking aging, chronic low-grade inflammation, cartilage matrix degradation, synovial inflammation, and subchondral bone remodeling, thereby playing central roles in OA pathogenesis. As a narrative review, this article aims to provide an integrated analysis of the cellular basis, molecular mechanisms, joint immune microenvironment, biomarkers, and immune reprogramming strategies related to inflammaging and immunosenescence in OA. Particular emphasis is placed on macrophage polarization, senescent cell clearance, SASP inhibition, and gene-editing approaches. This review highlights that future OA treatment may gradually shift from symptom-oriented management toward disease-modifying therapy based on the identification of immune endotypes. Nevertheless, further studies are required to validate the underlying molecular mechanisms, evaluate safety, and conduct clinical trials, thereby facilitating the clinical translation of immune reprogramming strategies for OA.
This review examines the biological foundations of inflammaging, emphasizing immunosenescence, senescence-associated secretory pathways, mitochondrial dysfunction, inflammasome biology, cytokine network dynamics, and epigenetic regulation, and proposes that inflammaging is best understood as multiscale biological interface failure.
Alejandro Melo-Florián, Alejandra Melo-Ramírez· Innovative Medicines & O...· 0 citations
Results support the idea that OA is an immunometabolic disease, and it is anticipated that this approach will control the immunometabolic dialogue, slow the advancement of osteoarthritis, end the vicious cycle of inflammatory metabolic disorders, and ultimately offer a new approach to treating osteoarthritis.
Ying Gao, Lan Shen, Xiaomei Su et al.· Frontiers in Pharmacology· 0 citations
Osteoarthritis (OA) is a common chronic degenerative joint disease characterized by progressive cartilage destruction, synovial inflammation, subchondral bone remodeling, and functional decline. Current treatments remain largely symptomatic and are unable to effectively halt or reverse disease progression. Increasing evidence indicates that epigenetic regulation provides a critical link between genetic susceptibility, mechanical loading, inflammation, aging, metabolic abnormalities, and pathological gene expression in OA. This review summarizes recent advances in OA epigenetics, with a particular focus on studies published over the past 2 years. We discuss classical mechanisms, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation, and further highlight emerging epigenomic layers such as chromatin accessibility, enhancer and super-enhancer remodeling, three-dimensional genome organization, tissue-specific regulation, and the integration of genetics with single-cell and spatial multi-omics. These mechanisms contribute to inflammatory activation, chondrocyte metabolic imbalance, extracellular matrix degradation, programmed cell death, cellular senescence, oxidative stress, and abnormal inter-tissue crosstalk. Epigenetic biomarkers and epigenetic-based interventions, including extracellular vesicle-mediated delivery, engineered RNA therapeutics, and small-molecule epigenetic drugs, may offer new opportunities for early diagnosis, disease stratification, and precision therapy. However, current studies are limited by model heterogeneity, sample variability, insufficient causal validation, limited reproducibility, and translational challenges related to delivery and safety. Overall, epigenetic regulation provides a systematic framework for understanding OA heterogeneity and progression and may promote the development of disease-modifying therapeutic strategies.
Yujing Zhao, Xianwen Liu· Frontiers in Genetics· 0 citations
Current evidence on the roles of miRNAs in OA is synthesized, focusing on their regulatory functions across joint tissues, including cartilage, synovium, subchondral bone, and the infrapatellar fat pad, along with their interactions with major inflammatory and degenerative signaling pathways.
Mujitapha Umar Safiyyu, Nazmul Huda Syed, M. Azlan et al.· Saudi Journal of Medicine an...· 0 citations
Because key cellular subsets and interaction programs may still retain partial plasticity during the early and middle stages of disease, stage-adapted modulation of these pathogenic networks may help restore synovial immune homeostasis, promote remission, delay disease progression, and reduce irreversible tissue damage.
Maozhi Feng, Hongtai Chen, Lu Liao et al.· Journal of Translational Med...· 1 citation
