Jul 2026· Saudi Journal of Medicine and Medical Sciences· Vol 14, pp. 197 - 208· 0 citations· 114 references
Medicine
TL;DR
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.
Abstract
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.
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 a chronic degenerative joint disease closely associated with aging and metabolic dysfunction, characterized by cartilage degeneration, synovial inflammation, aberrant subchondral bone remodeling, pain and progressive functional impairment. Beyond mechanical loading, accumulating evidence indicates that OA is increasingly recognized as a whole-joint disorder shaped by the interplay between local tissue damage and systemic endocrine-metabolic imbalance. Endocrine factors, including sex hormones, thyroid hormone, melatonin, parathyroid hormone and vitamin D, together with metabolic disturbances, such as obesity, insulin resistance, dysregulated glucose and lipid metabolism and gut microbiota imbalances, can cooperatively remodel the joint microenvironment. Mechanistically, these alterations converge on immuno-inflammatory amplification, mitochondrial dysfunction, oxidative stress, cellular senescence, metabolic reprogramming and regulated cell death, thereby promoting extracellular matrix degradation, persistent synovitis and uncoupled bone-cartilage remodeling. The present review systematically summarizes the molecular basis of endocrine-metabolic crosstalk in OA and discusses emerging therapeutic opportunities targeting hormonal signaling, metabolic pathways, circadian regulation, nutritional support and lifestyle interventions. Nevertheless, the reciprocal interactions among endocrine signals, systemic metabolic abnormalities and local joint pathology remain incompletely understood, and their translation into mechanism-based clinical stratification remains at an early stage. Thus, targeting endocrine-metabolic crosstalk may support mechanism-based phenotyping and subtype-informed precision therapy for OA, provided that candidate biomarkers and interventions are validated in prospective clinical studies.
Ruhui Yang, Haimin Zeng, Qi Xiao et al.· International Journal of Mol...· 1 citation
Osteoarthritis (OA) is a chronic degenerative joint disease characterized predominantly by articular cartilage degeneration, synovial inflammation, subchondral bone remodeling, and progressive impairment of joint function. Its pathogenesis is multifactorial and involves several interrelated pathological processes, including chronic low-grade inflammation, oxidative stress, dysregulated extracellular matrix metabolism, chondrocyte senescence and apoptosis, and microcirculatory dysfunction. At present, OA management remains largely focused on symptomatic relief, and disease-modifying agents capable of effectively delaying or reversing structural disease progression remain unavailable. As established HMG-CoA reductase inhibitors, statins exert a range of pleiotropic biological effects beyond lipid lowering, including anti-inflammatory and antioxidant actions, immunomodulatory activity, enhancement of endothelial function, and regulation of bone metabolism. These effects are closely aligned with the central pathogenic mechanisms implicated in OA. However, whether statins exert disease-modifying effects in OA, as well as the mechanisms underlying such effects, has not been systematically elucidated. In addition, current evidence is derived predominantly from in vitro experiments and animal models, whereas clinical evidence remains limited and heterogeneous. This review aims to evaluate the potential disease-modifying effects of statins in OA. Specifically, it systematically summarizes their mechanisms of action in the synovium, cartilage, subchondral bone, and vascular-metabolic microenvironment, reviews evidence from basic and clinical studies, and discusses the principal limitations and knowledge gaps in the current literature. Available studies indicate that statins may confer protective effects on OA-related tissues by modulating key pathological processes, including inflammation, oxidative stress, extracellular matrix metabolism, and bone remodeling. Nevertheless, robust high-quality clinical evidence supporting the use of statins as a disease-modifying therapeutic strategy for OA is still lacking. Future well-designed randomized controlled trials, integrated with disease phenotyping and biomarker-based investigations, are warranted to further define the clinical relevance, optimal target populations, and therapeutic value of different statin types, doses, and routes of administration.
Haitao Dong, Xianxu Zhang, Yannian Luo et al.· International Immunopharmaco...· 0 citations
Osteoarthritis (OA) is among the leading causes of disability worldwide, yet its pathogenesis remains incompletely understood. Once considered a "non-inflammatory" degenerative disorder, OA is now recognized as a condition driven by chronic low-grade inflammation. Emerging evidence implicates gut dysbiosis as a modifiable risk factor, promoting systemic inflammation through impaired gut permeability and translocation of microbial components. These immune-modulating molecules can trigger pro-inflammatory cascades and pathological bone remodeling. This review summarizes current knowledge linking gut dysbiosis and knee osteoarthritis and extends these insights to hip osteoarthritis (HOA). Observational and genetic studies support a causal role for the microbiota, identifying specific taxa associated with either increased or reduced HOA risk. Preclinical and clinical data describe a mechanistic axis linking intestinal dysbiosis, synovial inflammation, and cartilage degeneration. In animal models, particularly under high-fat/high-sucrose diets, visceral adiposity emerges as a major driver of joint damage. While microbial metabolites such as short-chain fatty acids appear protective, the detection of microbial DNA within joint tissues remains controversial, suggesting possible joint-specific microbial ecosystems. Based on these findings, microbiota-targeted strategies are under investigation as potential interventions to influence OA progression and relieve hip pain. However, longitudinal cohorts and randomized clinical trials in HOA are needed to clarify causal mechanisms and therapeutic efficacy in HOA.
Augusto Ferrini, Alessandro Del Monaco, B. Zampogna et al.· Orthopedic Reviews· 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
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.
Tong Wang, Wei Jiang, Xingxu Chen et al.· Frontiers in Immunology· 0 citations
