Inflammaging and immunosenescence-driven remodeling of the immune microenvironment in osteoarthritis: mechanisms, immune regulation and immune reprogramming
Aug 2026· Frontiers in Immunology· 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.
The concept of inflammaging—defined as the persistent, low-grade inflammatory state accompanying biological aging—has emerged as a unifying framework for understanding chronic disease in later life. Unlike acute inflammation, which is adaptive, transient, and protective, inflammaging reflects persistent dysregulation of immune signaling, impaired resolution of inflammatory responses, mitochondrial decline, and progressive loss of tissue homeostasis. Evidence increasingly indicates that inflammaging is not merely a consequence of aging but an active systems-level process that reshapes metabolic, vascular, neurological, and musculoskeletal physiology. Sustained inflammatory activation contributes to frailty, cardiovascular disease, neurodegeneration, sarcopenia, metabolic dysfunction, and osteoarthritis through interconnected molecular and cellular mechanisms involving immunosenescence, cellular senescence, oxidative stress, inflammasome activation, and epigenetic remodeling. Recent advances in geroscience have reframed inflammation as a multidirectional biological network integrating immune, endocrine, metabolic, microbiological, and biomechanical signals. This perspective moves beyond reductionist cytokine models by conceptualizing inflammation as a distributed regulatory architecture operating across tissues and organ systems. Accordingly, chronic disease may arise not only from local organ pathology but also from progressive failure of intersystem communication and adaptive resilience. This review examines the biological foundations of inflammaging, emphasizing immunosenescence, senescence-associated secretory pathways, mitochondrial dysfunction, inflammasome biology, cytokine network dynamics, and epigenetic regulation. We propose that inflammaging is best understood as multiscale biological interface failure, in which persistent inflammatory signaling progressively destabilizes tissue integration across physiological systems. This framework may support the development of more precise biomarkers, systems-oriented therapeutic strategies, and translational interventions designed to extend health span rather than merely prolong survival.
Alejandro Melo-Florián, Alejandra Melo-Ramírez· Innovative Medicines & O...· 0 citations
Prostate cancer is common in older men, yet mechanisms linking aging to tumor progression remain incompletely defined. Beyond genetic alterations, aging reshapes the prostate microenvironment through cellular senescence, chronic low-grade inflammation, immune dysfunction, stromal remodeling, metabolic stress, and impaired tissue repair, collectively promoting inflammaging. This persistent inflammatory state may create a permissive niche for tumor initiation, progression, immune evasion, and treatment resistance. Senescent epithelial and stromal cells release cytokines, chemokines, growth factors, matrix-remodeling enzymes, and extracellular vesicles through the senescence-associated secretory phenotype (SASP). In parallel, immune aging alters T-cell subsets, myeloid cells, macrophages, and anti-tumor surveillance. This review summarizes how SASP programs, Th17/Treg imbalance, IL-17/IL-23 signaling, myeloid remodeling, stromal aging, metabolic stress, and immune-stromal-epithelial crosstalk shape prostate cancer biology. We further discuss therapeutic implications, including cytokine modulation, senescence-directed therapy, metabolic intervention, and biomarker-guided strategies. This review highlights key knowledge gaps and proposes a framework for age-aware prostate cancer research, biomarker development, and therapeutic strategies.
Qiuyang Zhang, Keyi Shen, Sen Liu· Cells· 0 citations
Traditionally, osteoarthritis (OA) has been thought of as a degenerative disease mostly caused by mechanical wear and tear. However, recent research suggests that immunometabolic pathways drive the active process of subchondral bone remodeling. According to this study, the immunometabolic axis is a key regulatory network in the subchondral bone microenvironment of osteoarthritis (OA), facilitating metabolic interaction between osteocytes and immune cells like macrophages. Bone homeostasis is destroyed by immune cell infiltration, which also promotes the release of inflammatory mediators and local metabolic reprogramming. These results support the idea that OA is an immunometabolic disease. Intervening in the immunometabolic network of subchondral bone can be accomplished by focusing on immune cell metabolic pathways, particularly those that control the phenotypic transition of M1/M2 macrophages. 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
Osteoarthritis (OA) is the most prevalent degenerative joint disease and a leading cause of chronic pain and disability worldwide, particularly among aging populations. It is characterized by progressive degeneration of articular cartilage, synovial inflammation, subchondral bone remodeling, and metabolic alterations in the infrapatellar fat pad, reflecting pathology across the entire joint microenvironment. The onset and progression of OA are driven by complex interactions among mechanical stress, aging, obesity, and metabolic dysregulation, which collectively disrupt joint homeostasis. Mechanical injury and cartilage damage induce the release of damage-associated molecular patterns, activating innate immune receptors on chondrocytes and synovial cells. This promotes the production of pro-inflammatory mediators, including interleukin-1β, tumor necrosis factor-α (TNF-α), interleukin-6, and interleukin-17, which contribute to extracellular matrix degradation and cartilage deterioration. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, have emerged as key modulators in OA pathogenesis. They regulate chondrocyte proliferation, apoptosis, extracellular matrix turnover, inflammation, and osteochondral remodeling. Notably, certain miRNAs exhibit mechanosensitive properties, responding to altered biomechanical loading and translating mechanical stimuli into gene regulatory responses. This review synthesizes current evidence on the roles of miRNAs in OA, focusing on their regulatory functions across joint tissues, including cartilage, synovium, subchondral bone, and the infrapatellar fat pad. Key miRNAs such as miR-140, miR-146a, miR-27b, miR-34a, miR-155, and mechanosensitive miR-365 are discussed, along with their interactions with major inflammatory and degenerative signaling pathways. Their potential as diagnostic biomarkers and therapeutic targets is also highlighted.
Mujitapha Umar Safiyyu, Nazmul Huda Syed, M. Azlan et al.· Saudi Journal of Medicine an...· 0 citations
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive cartilage and bone destruction. Within the RA synovial microenvironment, resident synoviocytes, mesenchymal stem cells, fibroblasts, adipocytes, vascular-associated cells, and diverse immune cell populations form a dynamic interaction network through direct contact and paracrine mediators, including cytokines, chemokines, complement components, and extracellular vesicles. This review summarizes how these cellular interactions drive RA along a pathological continuum from early autoimmune initiation, through middle-stage inflammatory amplification and synovial hyperplasia, to late fibrosis, pannus formation, dysregulated bone remodeling, and irreversible structural damage. Particular emphasis is placed on the dynamic balance between pathogenic cellular circuits and immunoregulatory programs within the synovial microenvironment, which helps determine whether the joint remains in an inflammatory-active state, re-enters a remission-associated and relatively rebalanced state, or progresses toward remission failure and structural injury. We further discuss the major signaling pathways that mediate these interactions, especially NF-κB, MAPK, JAK-STAT, TGF-β/Smad, and Wnt/β-catenin signaling, highlighting how pathway crosstalk contributes to inflammatory persistence, loss of tissue plasticity, and progressive remodeling. Importantly, 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. A deeper understanding of stage-specific cellular programs and interaction networks may therefore provide a stronger theoretical basis for mechanism-informed precision therapies in RA.
Maozhi Feng, Hongtai Chen, Lu Liao et al.· Journal of Translational Med...· 0 citations
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
MIT News · Artificial Intelligence· news.mit.eduAug 17, 2026
