---
title: "Immuno-metabolic Crosstalk in Osteoarthritis: Mechanisms and Therapeutic Insights"
id: "frontiers-in-immunology-18-immuno-metabolic-crosstalk-in-osteoarthritis-from-mechanisms-to-therapies"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-18-immuno-metabolic-crosstalk-in-osteoarthritis-from-mechanisms-to-therapies"
content_type: "clinical_feed_article"
specialty: "Rheumatology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1946261"
published_at: "2026-10-01T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Immuno-metabolic Crosstalk in Osteoarthritis: Mechanisms and Therapeutic Insights
## Provenance & Clinical Metadata
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- **Specialty:** [Rheumatology](https://medichelpline.com/clinical-feed/rheumatology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1946261)
- **Published At:** 2026-10-01T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided source metadata identifies a review titled “Immuno-metabolic crosstalk in osteoarthritis: from mechanisms to therapies” published in Frontiers in Immunology. The URL and page header indicate this is a REVIEW article, but the body text of the article was not present in the supplied source. - The source material available to this task consisted principally of website navigation, journal sections, and links; substantive article content (abstract, introduction, methods, results, discussion, mechanistic details, and therapeutic recommendations) was not included. - Because the full article text and data were not provided, specific details about the proposed **immuno-metabolic** mechanisms in **osteoarthritis**, cellular or molecular pathways implicated, experimental findings, or candidate **therapies** are not available from the source and therefore are not reported here. - The DOI-like identifier appears in the URL (10.3389/fimmu.2026.1946261) and the article is presented as part of Frontiers in Immunology, but authorship, publication date, study design, evidence levels, and referenced studies were not supplied in the source text. - This summary does not infer or invent mechanistic pathways, trial outcomes, or therapeutic guidance; all substantive clinical or scientific claims are omitted because they were not present in the supplied source. - For clinicians or editors seeking to use this review as a reference, the original article should be accessed directly at the publisher site to retrieve full content, figures, and citations before applying any mechanistic or therapeutic assertions in practice or scholarship.
## Clinical Analysis & Structured Key Points
Frontiers | Immuno-metabolic crosstalk in osteoarthritis: from mechanisms to therapies REVIEW article Front. Immunol. , 01 October 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1946261 Published in Frontiers in Immunology Autoimmune Disorders 7 impact factor 11.3 citescore Part of a Research Topic Cell metabolism and bioactive metabolites in chronic inflammation Submission open 20k views 8 articles Editor & Reviewers Edited by C K Cyrus Khandanpour Reviewed by C S Chen-Yang Su P X Pengfei Xin Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Expression and pathological roles of mitochondrial dysfunction-related regulators in OA. View in article Table 2 Representative immunometabolic interventions in osteoarthritis: evidence from preclinical studies to clinical translation. View in article REVIEW article Front. Immunol. , 01 October 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1946261 Immuno-metabolic crosstalk in osteoarthritis: from mechanisms to therapies Y Y Yangfei Yi 1 K N Ke Ning 1 Y D Yitong Ding 1 F Y Fen Yang 1 Y L Yufei Li 1 * Y Z Yi Zhuo 1,2 * 1. School of Basic Medical Sciences Health Science Center Hunan Normal University, Changsha, China 2. School of Basic Medical Sciences/School of Nursing, Health Science Center, Hunan Normal University, Changsha, China Article metrics View details Abstract Background: Osteoarthritis (OA) is a heterogeneous whole-joint disorder influenced by mechanical stress, aging, previous trauma, genetic susceptibility, subchonrral bone alterations, and localized inflamation.Emerging evidence suggests that immune and metabolic processes alterations may be involved in OA pathogenesis particularly in inflammatory and metabolically dysregulated subtypes. Content: This narrative review summarizes the bidirectional crosstalk between immune and metabolic processes during OA progression. Human observational studies and experimental models suggest that immune-cell activation and metabolic dysfunction may interact to influence synovial inflammation and cartilage homeostasis although their causal relevance and relative contributions vary across OA phenotypes. We further discuss emerging immunometabolic strategies targeting glycolytic and lipid-metabolic pathways as well as predominantly experimental approaches involving gene editing synthetic biology and stem cell-based therapies. Conclusion: Integrating multi-omics technologies with personalized medicine may improve patient stratification and dynamic monitoring and could facilitate the future development of more personalized and potentially disease-modifying strategies for OA.Future research should focus on clarifying the dynamic immunometabolic network underlying OA and promoting the clinical translation of innovative strategies through artificial intelligence and interdisciplinary collaboration. 1 Introduction Osteoarthritis (OA), a prevalent chronic condition currently impacting more than 500 million people worldwide is increasingly recognized as a heterogeneous whole-joint disease rather than a single entity driven by a uniform pathogenic mechanism ( 1 , 2 ). The high prevalence of OA not only has a severe impact on the individual’s quality of life but also places a substantial burden on public health systems ( 3 ). OA is predominantly characterized by joint pain stiffness and functional limitations ( 4 ). As the disease advances patients frequently encounter a substantial reduction in their daily living and work capabilities, and prolonged suffering may also play a role in the development of psychological disorder ( 5 ). Current management strategies for OA primarily include pharmacological therapy, physical therapy, lifestyle interventions, and surgical treatment ( 6 ). Pharmacological management mainly relies on non-steroidal anti-inflammatory drugs (NSAIDs) to alleviate pain and improve symptoms ( 7 , 8 ). However, long-term use of these agents may be associated with gastrointestinal adverse effects and renal impairment ( 9 ). Despite substantial efforts to develop disease-modifying osteoarthritis drugs (DMOADs) ( 10 ), no generally accepted and approved pharmacological therapy has yet been demonstrated to reliably prevent or reverse OA progression ( 11 ) and most candidate DMOADs remain under clinical investigation. Physical therapy and exercise are also important components of OA management ( 11 – 13 ), although their effectiveness may be influenced by healthcare accessibility and patient adherence. In addition persistent joint pain and stiffness can restrict voluntary physical activity potentially contributing to further disease progression ( 14 , 15 ). These therapeutic limitations partly reflect the marked biological heterogeneity of OA.Historically osteoarthritis (OA) was largely considered a progressive cartilage wear disease resulting from mechanical overloading ( 16 ). Although biomechanical stress remains a major pathogenic factorthis model alone cannot fully account for the heterogeneity of OA. OA is now recognized as a complex whole-joint disease in which mechanical loading ageing previous injury genetic susceptibility local inflammation, and metabolic abnormalities contribute to varying degrees across different disease phenotypes. Accordingly, OA can be broadly categorized into mechanically driven OA post-traumatic OA age-related OA and metabolic OA. Mechanically driven OA is predominantly associated with elevated joint loading and biomechanical stress; post-traumatic OA develops following joint injury and is characterized by persistent inflammation; age-related OA is closely linked to cellular senescence mitochondrial dysfunction impaired tissue repair and age-associated low-grade inflammation; and metabolic OA is frequently associated with obesity insulin resistance dyslipidaemia adipokine imbalance and chronic systemic low-grade inflammation ( 17 ). These phenotypes are not mutually exclusive and may coexist or converge on shared downstream processes including synovial inflammation cartilage matrix degradation and subchondral bone remodelling. Therefore, within this heterogeneous framework immunometabolic dysregulation should be considered an important pathogenic dimension or endotypeparticularly in inflammatory and metabolically dysregulated OA phenotypes, rather than a universal mechanism underlying all forms of OA ( 18 ). Local inflammation is a common feature of OA whereas systemic low-grade inflammation is more evident in selected metabolic and inflammatory phenotypes ( 19 ). The joint cavity contains a substantial quantity of immune cells. The activation of these immune cells is closely associated with chronic inflammatory responses and may result in further damage to chondrocytes and other articular cells ( 20 ). An increase in pro‐inflammatory (M1) polarization within the synovium which is characterized by the elevated secretion of pro-inflammatory cytokines such as tumor necrosis factor‑α (TNF‑α) and interleukin‑1β (IL‑1β) not only intensifies local inflammatory responses in the synovial membrane but also disturbs articular cartilage metabolism resulting in heightened degradation and reduced regenerative capacity ( 21 ). Recent studies have revealed a marked imbalance in energy metabolism with osteoarthritis particularly within chondrocytes where dysregulated glycolysis and oxidative phosphorylation contribute to chondrocytes dysfunction. Metabolic dysregulation plays a significant role in the pathogenesis and progression of OA ( 22 ). This metabolic shift not only impairs the biosynthetic capacity of cartilage but also has the potential to trigger chronic inflammation by modulating the function of immune cells. In OA the levels of pro-inflammatory cytokines such as IL-6 and TNF-α are increased and metabolic signaling pathways including AMPK mTOR and PPARγ are intricately linked to OA pathology These pathways establish a complex regulatory network. IL-6 and TNF-α not only serve as key players in inflammation but also impact cellular metabolism by suppressing AMPK activity and enhancing mTOR activation thus promoting OA progression ( 23 ). Considering the multifactorial characteristics of OA pathogenesis single-target therapies have generally been ineffective ( 24 ). Against this backdrop immunometabolic modulation has emerged as a promising therapeutic approach. Recent reviews have examined the links between metabolism and inflammation in OA from different perspectives. Xia et al. focused on metabolic reprogramming and immunometabolic regulation in the context of ferroptosis ( 1 ). Liu et al. reviewed inflammation–metabolism crosstalk and emerging therapeutic strategies more broadly ( 25 ). Our review builds on this work by examining how immunometabolic dysregulation relates to distinct OA phenotypes and affects the joint as a whole. We do not assume that these processes contribute equally to all forms of OA.We discuss interactions among immune cells chondrocytes synovial fibroblasts and other joint-resident cells alongside the influence of obesity insulin resistance ageing and adipose tissue dysfunction. Where relevant we distinguish findings from OA studies from mechanistic insights obtained in other experimental or disease settings noting the limits of applying these findings to OA. We also assess emerging therapies according to their stage of clinical development and the evidence supporting their use. Particular attention is given to whether promising preclinical findings are supported by human studiesespecially randomized trials. Through this approach we aim to clarify how immunometabolic mechanisms may differ across OA phenotypes and where the evidence remains insufficient to guide treatment. 2 Literature search and selection This narrative review examines immunometabolic mechanisms and related therapeutic strategies in osteoarthritis (OA). We searched PubMed, Embase, and Web of Science from database inception to March 2026 and updated the searches in July 2026. No language restrictions were applied. Search terms covered five areas: OA, immunometabolism, immune and joint-resident cells, metabolic pathways, and therapeutic interventions. These included “osteoarthritis”, “osteoarthrosis”, “immunometabolism”, “metabolic reprogramming”, “macrophage”, “chondrocyte”, “synoviocyte”, “glycolysis”, “fatty acid oxidation”, “mitochondrial dysfunction”, “oxidative phosphorylation”, “AMPK”, and “mTOR.” Treatment-related terms included “metformin”, “gene editing”, “CRISPR”, “stem cells” and “exosomes.” Records from the three databases were combined and deduplicated before being reviewed by three authors. Publications were considered relevant if they addressed immune–metabolic interactions in OA or interventions targeting these processes. The review included human studies, OA-related animal experiments, in vitro and ex vivo studies, and relevant reviews. Evidence from other diseases was used only to explain background mechanisms and was distinguished from findings obtained directly in OA. Studies were prioritized according to the question being addressed. Human studies informed discussions of clinical associations and treatment outcomes, while experimental studies informed the assessment of mechanisms. Findings were interpreted with reference to the study population or model, design, and outcomes, with attention to negative results and differences between studies. The evidence was synthesized narratively, distinguishing clinical observations, experimental findings, and proposed mechanisms. This was not a systematic or scoping review, and some relevant publications may have been missed. 3 The immunological characteristics of OA For a considerable period OA has been recognized as a degenerative disorder mainly propelled by aging and mechanical stress which is characterized by the progressive deterioration of articular cartilage ( 26 ). Nevertheless in this process inflammation is not merely a secondary change in the advanced stages but rather plays a critical role in both disease initiation and sustained progression ( 27 ). The joint cavity contains a substantial population of immune cells primarily including neutrophils monocytes macrophages B cells T cells NK cells and dendritic cells ( 28 ). These cells not only participate in local immune responses but also significantly contribute to the pathological alterations within the joint ( 29 ). 3.1 Immunopathological alterations in OA The synovium is an important site of local inflammatory and immune responses during osteoarthritis progression ( 30 ). Histologically the synovium consists of an intimal lining layer and a sublining layer both of which may undergo structural remodeling in OA. OA-associated synovitis is characterized by varying degrees of synovial lining hyperplasia stromal fibrosis ( 31 ), vascular remodeling and inflammatory cell infiltration ( 28 ) 28 . Increased expression of pro-angiogenic mediators particularly vascular endothelial growth factor (VEGF) may promote neovascularization within the synovium ( 32 ). Synovitis is not merely a common pathological characteristic of OA but also a vital driver of cartilage degradation pain and disease progression ( 33 ). Researchers have identified a population of osteoclast-like cells in the synovium and interstitial fibrous layers. These cells which are characterized by the expression of RANKCTSK and MMP-9 are likely to be involved in joint destruction ( 34 ). Traditionally activated macrophages have been broadly classified into pro-inflammatory M1 and anti-inflammatory or tissue-reparative M2 phenotypes. Although the M1/M2 framework remains useful for describing macrophage responses in simplified in vitro systems and many preclinical OA studies, accumulating evidence indicates that this binary classification does not adequately capture the diversity of macrophage states present in human OA joints ( 35 ). The strength of evidence also varies across experimental settings. Mechanistic studies using cultured macrophages and animal models of OA suggest that macrophages with M1-like inflammatory features can enhance the production of TNF-α IL-1β and cartilage-catabolic mediators whereas M2-like or pro-resolving macrophage states may facilitate inflammatory resolution and tissue repair ( 36 ). However these experimentally induced polarization states should not be directly equated with discrete macrophage subsets in human OA synovium. Instead transcript omic and single-cell studies of human OA tissues have revealed diverse macrophage programs associated with inflammation phagocytosis tissue remodeling lipid metabolism and homeostatic functions ( 37 ). Importantly comparative analyses of synovial tissues from OA and rheumatoid arthritis (RA) indicate disease-specific differences in macrophage distribution and activation states ( 38 ). RA is generally characterized by more pronounced inflammatory macrophage activation whereas macrophages in OA display greater heterogeneity and mixed inflammatory–remodeling featuresr ( 39 ). Regulating pro-inflammatory macrophages can alleviate inflammation and mitigate the degradation of cartilage matrix. TRPV1a cation channel associated with pain perception and inflammation has been demonstrated to reduce the polarization of pro-inflammatory, thereby ameliorating OA ( 40 ). Through the restoration of mitochondrial membrane potentialthe elevation of glutathione (GSH) levelsand the promotion of intracellular autophagy, pro-inflammatory were effectively repolarized to an anti-inflammatory. This repolarization augmented chondrocyte proliferation and viability concurrently suppressing apoptosis ( 41 ). In the early stage of OA the subchondral bone plate experiences thinning along with an increase in porosity which is accompanied by heightened bone resorption activity. Osteoclasts facilitate angiogenesis and nerve ingrowth through the release of factors such as TGF‑β1 and H + . Simultaneously they activate immune cells including pro-inflammatory, thus establishing a pro‑inflammatory microenvironment ( 42 ). Concurrently osteocytes increase the RANKL/OPG ratio and osteoblasts secrete mediators such as IL‑6 and PGE2, which further promotes osteoclast differentiation and sustains the inflammatory cycle. Immune cells and stromal cells establish a complex network mediated by metabolites and cytokines within which the osteoclast-chondrocyte crosstalk serves as a crucial pathological link. Osteoclasts facilitate chondrocyte hypertrophy and apoptosis through signaling via exosomes and other pathways. Meanwhile chondrocytes recruit and activate osteoclasts by releasing factors such as CXCL12 and HMGB1, thereby establishing a vicious cycle ( 43 ). The acidic microenvironment the release of damage‑associated molecular patterns (DAMPs). and the upregulation of nerve growth factor (NGF) further exacerbate pain and immunometabolic dysregulation ( 44 ). Therefore the immune microenvironment in OA is characterized by a complex and interrelated state of imbalance which serves as the core pathological basis for driving disease progression and pain. 3.2 Key immune cells and inflammatory mediators T and B cells have been identified in OA synovial tissue with their abundance and activation profiles varying across patients and disease stages ( 45 ). Studies of human OA joints have reported changes in CD4 + and CD8 + T-cell populations including Th1Th17and regulatory T (Treg) cells ( 46 ). Th1- and Th17-associated cytokines may contribute to local inflammatory signaling whereas Treg cells may limit inflammation through mediators such as IL-10 and TGF-β ( 47 ). B-cell infiltration and occasional lymphoid aggregates have also been observed in subsets of OA synovial samples although their contribution to disease progression remains uncertain. These findings suggest adaptive immune involvement in selected OA phenotypes rather than establishing a universal antigen-driven or immune-complex-mediated disease mechanism. During the recruitment of inflammatory cells neutrophils release pro‑inflammatory cytokines such as IL‑1β and IL‑6generate reactive oxygen species and engage in the activation of matrix‑degrading enzymes, which collectively contribute to cartilage destruction ( 48 ) stimulated chondrocytes produce MMPs, TNF-α, IL-6 and IL-8 leading to the degradation of the extracellular matrix ( 49 ). Inflammatory stimuli activate nerve endings which leads to joint pain ( 50 ). Meanwhile neovascularization and cellular infiltration continuously sustain the inflammatory process thereby establishing a vicious cycle ( 51 ). TNF-α and IL-1β are among the most extensively studied inflammatory mediators in OA. Elevated levels of these cytokines have been detected in the synovial tissue and synovial fluid of subsets of patients with OA. Experimental studies indicate that TNF-α and IL-1β can enhance inflammatory signaling and promote catabolic responses in chondrocytes by increasing matrix-degrading enzymes such as MMPs while suppressing extracellular matrix synthesis. However their concentrations and biological effects vary across patients disease stages and experimental settings and neither cytokine alone is sufficient to account for the heterogeneous pathogenesis of OA. ( Figure 1 ). Figure 1 Local tissue alterations and immune features in osteoarthritis and their potential associations with systemic inflammatory factors. The left panel illustrates selected features of the local osteoarthritis (OA) joint microenvironmen tincluding synovial inflammation and vascular remodeling in filtration of immune-cell populations cartilage extracellular matrix degradation chondrocyte apoptosis subchondral bone remodeling and neurovascular changes ( 26 , 28 ). Pro-inflammatory macrophage states and adaptive immune-cell populations including Th17 cells may contribute to local inflammatory and catabol
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