Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Osteoarthritis. Core disease mechanisms, molecular and cellular pathways,...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis

• Authors: Matko Rošin, Nela Kelam, Ivana Jurić, Anita Racetin, Marin Ogorevc et al.
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/57841664d6504d9f79e616859c2bbf8060941c4f
• DOI: 10.3390/ijms25084557
• PMID: 38674142
• PMCID: 11049902
• Citations: 8
• Summary: Hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.
• Evidence snippets:
• Snippet 1 (score: 0.510) > Osteoarthritis (OA) is the most common form of arthritis. It can affect any joint but typically involves the knees and hips. It is one of the most common and important causes of chronic pain and disability. It severely impacts patients' quality of life and increases the socioeconomic burden [1][2][3]. Globally, hip and knee OA was ranked among the highest contributor to global disability in disability-adjusted life years [4][5][6]. > According to the Osteoarthritis Research Society International's definition of OA, OA is a disorder of mobile joints illustrated by the cellular degradation of the extracellular matrix through micro-and macro-injuries that initiate adaptive repair mechanisms, including pro-inflammatory pathways of innate immunity. The disorder manifests itself first at the molecular level (impaired metabolism of joint tissues), and then through anatomical and physiological impairment (cartilage degradation, bone remodelling, osteophyte formation, and joint inflammation), resulting in loss of joint function and disease manifestation [5]. It is important to note that OA is not a pathophysiologically exclusive disease but rather a diverse syndrome with altered clinical phenotypes that affects all joint structures, eventually leading to common clinical manifestations [6][7][8]. OA can be divided into primary (idiopathic) and secondary OA [9]. Secondary OA is commonly caused by post-traumatic, dysplastic, infectious, inflammatory, or biochemical events [10]. > Primary OA was long thought to be a disease caused by prolonged and overloaded articular cartilage wear and tear. However, the current understanding of the disease shows that pathological changes involve cartilage, bone, synovium, ligaments, fat tissues, menisci, and neurological pathways involved in pain processing. The changes occur not only due to mechanical overloads, but also due to metabolic and genetic factors that result in inflammation [11]. Therefore, synovial inflammation is often present in both early OA and advanced OA and is implicated in the OA development and progression. Synovial cells produce molecules that enable synovial inflammation and lead to cartilage damage during OA progression [12].

[2] CD19, ALDH18A1, and CACNA1G as Significant Hub Genes in End-Stage Osteoarthritis

• Authors: Mahshid Malakootian, Akram Gholipour, Maziar Oveisee
• Year: 2023
• Venue: Iranian Journal of Public Health
• URL: https://www.semanticscholar.org/paper/7d41a436833eebece8fa22d60c6d18a0fde7a459
• DOI: 10.18502/ijph.v52i12.14326
• PMID: 38435769
• PMCID: 10903304
• Citations: 4
• Summary: This study is the first to provide fresh insights into the potential therapeutic targets of key genes, namely CD19, CACNA1G, and ALDH18A1, differentially expressed in end-stage osteoarthritis and their relevant signaling pathways and interactive microRNAs.
• Evidence snippets:
• Snippet 1 (score: 0.477) > Osteoarthritis is the most prevalent degenerative joint disease that affects the knee, hip, and small finger joints, leading to chronic pain, limited joint movement, and joint deformity in the elderly (1)(2)(3)(4). Treatment approaches to impede or reverse osteoarthritis are limited by its long-term nature, diagnosis time, and numerous associated mechanisms (1)(2)(3). In osteoarthritis development, affected joints predominantly undergo articular cartilage degen-eration, osteophyte formation, subchondral sclerosis, synovitis, and meniscus degeneration, reflecting the complication of osteoarthritis pathogenic mechanisms (2)(3)(4). Factors contributing to osteoarthritis development and progression include trauma, aging, obesity, fracture, surgery, ligament tear, and genes (5)(6)(7)(8). Nonetheless, the exact pathogenesis underlying osteoarthritis has yet to be determined, hence the need for fresh insights into the genes and pathways is of great importance. Recent advanced approaches, such as genomewide association, candidate gene, and global gene expression analyses via microarray and RNAsequencing techniques, help understand the pathogenesis of musculoskeletal diseases, including osteoarthritis (9)(10)(11)(12)(13). Bioinformatics studies can provide comprehensive data on gene expression alterations in messenger RNAs (mRNAs) in early and end-stage knee osteoarthritis and introduce specific gene hubs in its pathophysiology. Accordingly, we conducted the present study to 1) determine differentially expressed gene profiles and perturbed molecular functions and pathways in early and end-stage osteoarthritis via a functional enrichment analysis, 2) uncover differentially expressed protein-protein interaction (PPI) networks through a PPI analysis, 3) reveal hub genes in a network analysis, and 4) analyze mi-croRNA (miRNA) regulatory binding sites using the miRcode database to provide a list for each hub gene.

[3] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.463) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[4] Icariin: A Potential Molecule for Treatment of Knee Osteoarthritis

• Authors: Jun-tao Zhang, Fangyang Fan, Aifeng Liu, Chao Zhang, Qi Li et al.
• Year: 2022
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/745d90efb977d0c8c4ffc837c396aefc8b95967b
• DOI: 10.3389/fphar.2022.811808
• PMID: 35479319
• PMCID: 9037156
• Citations: 43
• Influential citations: 2
• Summary: The molecular mechanism of ICA for the treatment of KOA is revealed, demonstrating its potential value for further research and as a new drug.
• Evidence snippets:
• Snippet 1 (score: 0.462) > Background: Knee osteoarthritis (KOA) is a degenerative disease that develops over time. Icariin (ICA) has a positive effect on KOA, although the mechanism is unknown. To investigate drug-disease connections and processes, network pharmacology is commonly used. The molecular mechanisms of ICA for the treatment of KOA were investigated using network pharmacology, molecular docking and literature research approaches in this study. Methods: We gathered KOA-related genes using the DisGeNET database, the OMIM database, and GEO microarray data. TCMSP database, Pubchem database, TTD database, SwissTargetPrediction database, and Pharmmapper database were used to gather ICA-related data. Following that, a protein-protein interaction (PPI) network was created. Using the Metascape database, we performed GO and KEGG enrichment analyses. After that, we built a targets-pathways network. Furthermore, molecular docking confirms the prediction. Finally, we looked back over the last 5 years of literature on icariin for knee osteoarthritis to see if the findings of this study were accurate. Results: core targets relevant to KOA treatment include TNF, IGF1, MMP9, PTGS2, ESR1, MMP2 and so on. The main biological process involved regulation of inflammatory response, collagen catabolic process, extracellular matrix disassembly and so on. The most likely pathways involved were the IL-17 signaling pathway, TNF signaling pathway, Estrogen signaling pathway. Conclusion: ICA may alleviate KOA by inhibiting inflammation, cartilage breakdown and extracellular matrix degradation. Our study reveals the molecular mechanism of ICA for the treatment of KOA, demonstrating its potential value for further research and as a new drug.

[5] Knee Osteoarthritis—How Close Are We to Disease-Modifying Treatment: Emphasis on Metabolic Type Knee Osteoarthritis

• Authors: S. Lambova
• Year: 2023
• Venue: Life
• URL: https://www.semanticscholar.org/paper/40481a4f18e0f7795a5386b8c4b1711d9c98845f
• DOI: 10.3390/life13010140
• PMID: 36676089
• PMCID: 9866724
• Citations: 5
• Summary: Osteoarthritis (OA) is a whole-joint disease that affects cartilage, bone, and synovium as well as ligaments, menisci, and muscles [...].
• Evidence snippets:
• Snippet 1 (score: 0.457) > The heterogeneous nature of OA regarding localization and its dominant pathogenic mechanism are the major causes for unsatisfactory therapeutic results in relation to slowing of structural progression. The standard pharmacological treatments used in OA are nonsteroidal anti-inflammatory drugs, analgesics, and symptomatic, slow-acting agents with chondroprotective properties (e.g., glucosamine, chondroitin, soy and avocado, and intraarticular hyaluronic acid) [2,3]. > The knee is the most commonly affected joint in OA. The existence of different phenotypes of knee OA has been suggested; however, the precise criteria for their classification are not well-defined. While clinical phenotypes are characterized by common risk factors and can be used to determine progression and predict therapeutic response, the endotypes are disease subtypes characterized by well-defined molecular mechanisms, i.e., cellular and biochemical signaling pathways [4]. > Based on a systematic literature review, Dell'Isola et al. (2016) have proposed the existence of six phenotypes of knee OA related to predominant pathogenic mechanisms, i.e., a chronic pain phenotype, an inflammatory phenotype, phenotypes associated with alterations in bone and cartilage metabolism, with metabolic syndrome, a mechanical phenotype, and minimal joint disease. The chronic pain phenotype is thought to be related to central sensitization and alterations in pain neurophysiology and the psychological profile. Regarding the inflammatory type of knee OA, gene overexpression of inflammatory cytokines was detected, e.g., interleukin (IL)-1β, cyclooxygenase 2, and macrophage-inflammatory proteins. Higher level of pain and faster radiographic progression were observed in these cases compared to those with low cytokine expression. In the metabolic type of knee OA, it has been suggested that metabolic syndrome contributes to the development of knee OA, and this phenotype has been associated with higher levels of leptin and high-sensitivity CRP (hsCRP).

[6] Putative functional variants of PI3K/AKT/mTOR pathway are associated with knee osteoarthritis susceptibility

• Authors: Kejie Wang, M. Chu, Feng Wang, Yiwen Zhao, Haifeng Chen et al.
• Year: 2020
• Venue: Journal of Clinical Laboratory Analysis
• URL: https://www.semanticscholar.org/paper/8aaf33d439ae4407ca10451320ebf7668f3c2c6a
• DOI: 10.1002/jcla.23240
• PMID: 32052902
• PMCID: 7307371
• Citations: 12
• Summary: Strong evidence leads to the understanding that P13K/AKT/mTOR signaling is very important in cartilage degeneration.
• Evidence snippets:
• Snippet 1 (score: 0.455) > Osteoarthritis (OA) is a kind of musculoskeletal disease which influence the bone, synovial tissues, and articular cartilage with no obvious regional and racial difference. 1 Over million people are affected by OA worldwide, and it is an important reason for long-term immortality in China. 2,3 OA commonly affects various human joints, and knee joints are most vulnerable. Pathology characteristics of knee osteoarthritis (KOA) are cartilage degeneration, cartilage extracellular matrix (ECM) deterioration, subchondral bone sclerosis, and synovitis. 4,5 The clinical manifestations of KOA are joint swelling, pain, malformation, and lose of motion. 6 KOA brings huge burden to family and society all over the world. 7 Thus, it is urgent to explore detail pathophysiology and molecular biology mechanism of OA for early diagnosis and treatment. > The etiology of osteoarthritis has not been fully understood. Risk factors such as obesity, genetics, family susceptibility, local biomechanics, age, and previous trauma may lead to OA occurrence and progression. 8 As the sole cell type in joint cartilage, the imbalance between apoptosis and proliferation of chondrocytes is very important for OA. 9 Therefore, keeping the homeostasis between apoptosis and proliferation of chondrocytes may facilitate cartilage repair and symptoms relieve of OA PI3K/AKT/mTOR pathway has received substantial attentions because it plays a crucial role during several characteristic alterations of cartilage such as expression of matrix metalloproteinase (MMP) or a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) which will finally lead to the apoptosis of chondrocytes. 10 PI3K/AKT/mTOR pathway belongs to serine/threonine protein kinase family.

[7] Multifaceted imaging strategies for clinical trials of knee osteoarthritis—a tightly interlinked value and precision chain

• Authors: F. Eckstein, A. Mobasheri, M. Boesen
• Year: 2025
• Venue: Skeletal Radiology
• URL: https://www.semanticscholar.org/paper/78f6803dea72ef5c7a9956bd629c6787ea1a7ad7
• DOI: 10.1007/s00256-025-04919-0
• PMID: 40167617
• PMCID: 12241129
• Citations: 6
• Summary: Osteoarthritis is a debilitating, whole-organ disease that involves all osteoarticular tissues. No effective treatments have yet been approved by the regulatory agencies for modifying the natural history of this disease and its structural progression. In this whitepaper, we will summarize concepts of “multi-faceted” (multi-contrast) magnetic resonance imaging (MRI), with a focus on its application in osteoarthritis clinical trials. The process described here encompasses a tightly interlinked...
• Evidence snippets:
• Snippet 1 (score: 0.451) > Osteoarthritis is the most common form of arthritis and affects more than 500 million people worldwide; it causes medical expenditures in the order of 2.5% of the gross domestic product [1]. It is a serious and highly debilitating whole-organ, multi-tissue disease [2], and thus far no disease-modifying osteoarthritis drug (DMOAD) has been approved. Clinical management is hence focused on controlling symptoms and function, e.g., by weight loss, strength exercise for maintaining muscle function, and pain medication. Yet, the efficacy of these measures is limited, and chronic pain management involves health risks [3,4]. Osteoarthritis has been identified as a heterogeneous disease, i.e., in terms of severity, natural history, and treatment response [5], and may be stratified into multiple subtypes in a primary healthcare setting, i.e., into clinically apparent phenotypes [6][7][8]. Its heterogeneity may reflect different underlying mechanisms, i.e., molecular endotypes (molecular, cellular, immunological, genetic, and genomic features) that may drive disease pathogenesis, incidence, and progression [6][7][8]. (Table 1). Genotypes can influence anatomical shapes, configurations, and their pathology (i.e., morphotypes) as well as associated disease mechanisms (endotypes), knowledge of which offers opportunity to match these underlying disease mechanisms to an investigational medicinal product's mode of action (MOA), and certain "theratypes" (therapeutic subtypes) [6][7][8]. (Table 1). "Imaging phenotypes" represent observable characteristics or traits (faces or "facets") of tissues, organs, or entire organisms captured through current medical imaging techniques, and similarly to "clinical phenotypes," these may be used for subtyping disease [9][10][11][12] (Table 1).

[8] New Trends in Pharmacological Treatments for Osteoarthritis

• Authors: Xiaoyan Cai, S. Yuan, Yanting Zeng, Cui-mei Wang, Na Yu et al.
• Year: 2021
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/880808ac1d5df381c0da3566eaf6bc5dc7f8dd88
• DOI: 10.3389/fphar.2021.645842
• PMID: 33935742
• PMCID: 8085504
• Citations: 89
• Influential citations: 1
• Summary: A narrative review will discuss recent developments of agents for the treatment of OA, including potential disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics for pain relief and attractive drugs with potential applications in preclinical research.
• Evidence snippets:
• Snippet 1 (score: 0.451) > Osteoarthritis (OA) is the leading cause of function loss and disability among the elderly, with significant burden on the individual and society. It is a severe disease for its high disability rates, morbidity, costs, and increased mortality. Multifactorial etiologies contribute to the occurrence and development of OA. The heterogeneous condition poses a challenge for the development of effective treatment for OA; however, emerging treatments are promising to bring benefits for OA management in the future. This narrative review will discuss recent developments of agents for the treatment of OA, including potential disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics for pain relief. This review will focus more on drugs that have been in clinical trials, as well as attractive drugs with potential applications in preclinical research. In the past few years, it has been realized that a complex interaction of multifactorial mechanisms is involved in the pathophysiology of OA. The authors believe there is no miracle therapeutic strategy fitting for all patients. OA phenotyping would be helpful for therapy selection. A variety of potential therapeutics targeting inflammation mechanisms, cellular senescence, cartilage metabolism, subchondral bone remodeling, and the peripheral nociceptive pathways are expected to reshape the landscape of OA treatment over the next few years. Precise randomized controlled trials (RCTs) are expected to identify the safety and efficacy of novel therapies targeting specific mechanisms in OA patients with specific phenotypes.

[9] The interplay between dysregulated metabolites and signaling pathway alterations involved in osteoarthritis: a systematic review

• Authors: A. Aziz, Kavitha Ganesan Nathan, T. Kamarul, A. Mobasheri, Alimohammad Sharifi
• Year: 2024
• Venue: Therapeutic Advances in Musculoskeletal Disease
• URL: https://www.semanticscholar.org/paper/6188911fbcc8ee58abd6f0343a335320b45647dc
• DOI: 10.1177/1759720X241299535
• PMID: 39600593
• PMCID: 11590150
• Citations: 9
• Influential citations: 1
• Summary: A systematic review of literature published between August 2017 and May 2024 reveals a complex interplay between dysregulated metabolites and signaling pathways in OA, offering potential biomarkers and therapeutic targets.
• Evidence snippets:
• Snippet 1 (score: 0.450) > , mitogen-activated protein kinase, Wnt/β-catenin, and mammalian target of rapamycin, were associated with changes in metabolite levels, particularly in proinflammatory lipids and energy-related compounds. Conclusion: This review reveals a complex interplay between dysregulated metabolites and signaling pathways in OA, offering potential biomarkers and therapeutic targets. Further research is needed to explore the molecular mechanisms driving these changes and their implications for OA treatment. Plain language summary Understanding how altered metabolites and signaling pathways contribute to osteoarthritis: a comprehensive review Aims and purpose of the research Research question: The main question we are exploring is how certain chemicals in the body, called metabolites, are linked to signaling pathways in osteoarthritis (OA). Hypotheses/Expectations: Before starting this review, we expected that specific metabolites would be connected to the processes that cause OA, like inflammation and cartilage tissue breakdown. Objective: Our goal is to identify these metabolites and understand how they interact with signaling pathways in OA. We aim to gather data from various sources, including laboratory experiments, animal studies, and human clinical studies. Background of the research Why this question matters: Osteoarthritis is a common and painful condition that affects the joints, making it hard for people to move and perform everyday tasks. There are not many effective treatments available, which is why it’s important to study this disease in depth. By understanding the metabolic changes that occur in OA, we might find new ways to treat it. Scale of issue: Osteoarthritis affects millions of people around the world. It is a leading cause of disability and significantly impacts the quality of life of those who suffer from it. The high prevalence and limited treatment options make it a major public health issue. Methods and research design Research design: We conducted a systematic review of scientific literature published between August 2017 and May 2024. This means we carefully collected and analyzed all relevant studies available in major databases like PubMed, Scopus, Web of Science, and Google Scholar. We followed strict guidelines (PRISMA) to ensure our review was thorough and unbiased. Key variables: The key variables in our study were different types of metabol

[10] Downregulation of miR-34a Promotes Proliferation and Inhibits Apoptosis of Rat Osteoarthritic Cartilage Cells by Activating PI3K/Akt Pathway

• Authors: Haitao Tao, Lei Cheng, Ruixiang Yang
• Year: 2020
• Venue: Clinical Interventions in Aging
• URL: https://www.semanticscholar.org/paper/335a24682469fdc80799782badcc9eeaa625a2df
• DOI: 10.2147/CIA.S241855
• PMID: 32214804
• PMCID: 7084127
• Citations: 17
• Influential citations: 1
• Summary: Downregulation of miR-34a regulated proliferation and apoptosis of cartilage cells by activating PI3K/Akt pathway, providing a potential therapeutic approach for the treatment of osteoarthritis.
• Evidence snippets:
• Snippet 1 (score: 0.445) > Osteoarthritis is a degenerative joint disease that can ultimately lead to joint damage. 1 Articular cartilage degeneration, subchondral sclerosis and synovial inflammation are the characteristics of osteoarthritis. 2The etiology of osteoarthritis is multifactorial, including aging, strain, trauma, infection, obesity, joint congenital anomalies, metabolic disease, and so on. 3,4Osteoarthritis increases with the prolongation of lifespan and has become one of the global clinical problems that burden patients and health care systems. 5Although osteoarthritis has received attention from researchers in terms of drug development and physical exercise, the therapeutic effect is still unsatisfactory. 6,7Therefore, it would be of great clinical value to find new molecularly targeted drugs or new therapeutic target that can effectively treat osteoarthritis. > MicroRNAs (miRNAs) are short noncoding RNAs molecules (19-25 nucleotides length) that regulate the expression of many human-protein-coding genes. 8iRNA plays an important role in a variety of biological processes by bind to the complementary sequences in the 3ʹ untranslated region to involve the post-transcriptional regulation. 9,10miR-34a is a member of the miR-34 family and is the most significantly regulated downstream miRNA of the p53 pathway. 113][14] The crucial role of miRNA in various diseases is related to their regulation of essential cellular processes and pathways. 15Previous studies have demonstrated that an apoptosis activation by the intrinsic and extrinsic way might be due to a protection mechanism after sublethal injury. 16,17The phosphatidylinositol-3-kinase-protein kinase B (PI3K/Akt) mediated signaling is one of the most critical pathways in regulation of cellular survival, proliferation, differentiation and apoptosis. 18Growth factors and hormones trigger PI3K phosphorylation events, which in turn coordinate cell growth, cell cycle entry, cell migration and cell survival. 19Moreover, the PI3K pathway inhibits the cell cycle progression by repressing downstream molecule Akt. 19

[11] RNA Modifications in Osteoarthritis: Epitranscriptomic Insights into Pathogenesis and Therapeutic Targets

• Authors: Shabnam Radbakhsh, Mehdi Najar, Makram Merimi, M. Benderdour, Julio C Fernandes et al.
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/835acb058b9a87c0633e783ea13c72e077410361
• DOI: 10.3390/ijms26104955
• PMID: 40430096
• PMCID: 12112650
• Citations: 5
• Summary: This is the first review comprehensively addressing all epitranscriptomic modifications in OA and it is shown that disruption in these modifications can interfere with gene expression and protein function.
• Evidence snippets:
• Snippet 1 (score: 0.443) > Osteoarthritis (OA) is a complex, multifactorial chronic disorder affecting the entire joint, including bone and cartilage, leading to reduced mobility and disability [1]. Based on the Global Burden of Disease 2021 estimates, OA affected 7.6% of the global population, representing approximately 595 million individuals, with a higher prevalence in women than in men [2]. Pharmacological medicines mainly provide relief from symptoms, and no definitive therapy exists to stop the progression of the disease [3]. Although the precise mechanisms underlying OA are not yet fully understood, inflammation and cartilage degeneration through matrix metalloproteinases (MMPs) enzymes and a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAMTS) family proteins are the main contributors to OA pathogenesis [4,5]. Multiple molecular pathways are implicated in the development of OA. The Wnt/β-catenin and TGF-β/SMAD pathways, which regulate chondrocyte homeostasis and cartilage metabolism; the NF-κB and MAPK pathways, which mediate inflammatory responses; along with the Akt/mTOR/PI3K and oxidative stress pathways, which contribute to autophagy, chondrocyte apoptosis, and extracellular matrix (ECM) degradation, are considered among the main pathways involved in OA [6,7]. > Genetics plays a significant role in the development of OA and involves the interplay of multiple genes [8,9]. Over 100 genomic risk loci associated with OA have been identified in large-scale genome-wide association studies (GWAS) [10]. Type II collagen (COL2A1), COL9A2, COL11A1, COL11A2, COL1A1, COMP, AGC1, and TGFβ1, which are related to cartilage metabolism, and inflammatory genes that encode cytokines such as interleukin-1 alpha (IL1A) and IL1B, are key genes related to OA [11][12][13].

[12] Unraveling the Scientific Landscape of Osteoarthritis: Dynamics of Publications over Five Decades

• Authors: Roxana Pavel, A. Radu, Ada Radu, Bogdan Uivaraseanu, Gabriela Bungau et al.
• Year: 2025
• Venue: Bioengineering
• URL: https://www.semanticscholar.org/paper/4b6440b9126971a453b67dc4f23419d532552fae
• DOI: 10.3390/bioengineering12060602
• PMID: 40564418
• PMCID: 12189298
• Citations: 1
• Summary: This bibliometric assessment underscores exponential growth in osteoarthritis research and highlights the urgent need for more personalized, multidimensional evaluation strategies to enhance clinical translation.
• Evidence snippets:
• Snippet 1 (score: 0.443) > The global rise in osteoarthritis incidence can be primarily attributed to demographic shifts, particularly an aging population, along with the escalating rates of obesity. This condition, recognized for its heterogeneity, poses a significant public health challenge due to its growing prevalence and associated disability. Recent research has deepened understanding of osteoarthritis, highlighting genetic factors, gut microbiota, and varied pain mechanisms as key contributors [1]. The anatomical regions most frequently implicated in osteoarthritis are the load-bearing joints, particularly the knee, hip, and lumbar spine, while the hand serves as a representative example of a non-load-bearing joint that is also commonly affected [2]. > The etiology of osteoarthritis is multifactorial, involving diverse biological and mechanical contributors. Its complex pathogenesis is driven by a combination of mechanical, genetic, metabolic, inflammatory, and aging-related factors. Mechanical stress, often due to abnormal joint loading, malalignment, or injury, contributes to cartilage breakdown by inducing chondrocyte apoptosis and extracellular matrix degradation [3]. Genetic susceptibility plays a critical role in osteoarthritis development, with multiple gene variants influencing cartilage homeostasis and inflammatory pathways, explaining interindividual variability in disease onset and progression [4]. Osteoarthritis has been categorized into six primary phenotypes, each reflecting distinct pathophysiological pathways, including a chronic pain phenotype involving central sensitization, an inflammatory phenotype, a form associated with metabolic syndrome, a subtype characterized by altered bone and cartilage metabolism, a mechanically driven phenotype related to joint malalignment, and a phenotype with minimal joint structural changes, often presenting with milder clinical features [5]. > Metabolic syndrome components such as obesity, insulin resistance, and dyslipidemia further exacerbate osteoarthritis through systemic low-grade inflammation and altered adipokine secretion, which negatively impact cartilage metabolism and promote catabolic signaling within the joint [6]. Inflammation, previously considered secondary, is now recognized as a key driver of osteoarthritis pathology.

[13] Unraveling Osteoarthritis: Mechanistic Insights and Emerging Therapies Targeting Pain and Inflammation

• Authors: M. Alad, Fajer Yousef, L. Epure, Angelina Lui, M. Grant et al.
• Year: 2025
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/1bc9cf4a71623956fc1b7d3c9b6064f136a73537
• DOI: 10.3390/biom15060874
• PMID: 40563514
• PMCID: 12191023
• Citations: 8
• Summary: This review explores the complex pathophysiology of OA with a focus on the emerging mechanisms of pain and inflammation that extend beyond articular cartilage degradation, and integrates molecular and cellular mechanisms to highlight innovative therapies aimed at modifying both the structural damage and neurosensory drivers of pain.
• Evidence snippets:
• Snippet 1 (score: 0.442) > Osteoarthritis (OA) is now widely recognized not merely as a cartilage-centric disease but as a multifactorial disorder affecting the entire joint as an organ, including the articular cartilage, subchondral bone, synovium, ligaments, menisci, and the innervating neural elements. This review explores the complex pathophysiology of OA with a focus on the emerging mechanisms of pain and inflammation that extend beyond articular cartilage degradation. Joint inflammation driven by immune activation in response to cellular stress signals promotes the release of pro-inflammatory mediators and catabolic enzymes. Key signaling pathways such as NF-κB, MAPKs, and JAK/STAT amplify these responses, and pain is sustained through peripheral and central sensitization, contributing to exacerbating symptoms even in the absence of visible joint damage. This review also integrates molecular and cellular mechanisms to highlight innovative therapies aimed at modifying both the structural damage and neurosensory drivers of pain. These approaches offer the potential to not only alleviate symptoms but also alter disease progression, signaling a move toward personalized, mechanism-based treatments. Given the intricate interactions among joint tissues, immune activation, and sensory processing, a comprehensive strategy that targets both structural degeneration and neuroinflammation is essential for the future of OA management. Emphasizing the joint as an integrated organ, we advocate for translational research linking molecular pathology with clinically meaningful outcomes.

[14] The Interplay of Aging and PANoptosis in Osteoarthritis Pathogenesis: Implications for Novel Therapeutic Strategies

• Authors: Shaoshan Liu, Guifeng Zhang, Nan Li, Zheng Wang, Liaodong Lu
• Year: 2025
• Venue: Journal of Inflammation Research
• URL: https://www.semanticscholar.org/paper/6a9edd2de5d7a7966db02dd56b556abef0f8a1e4
• DOI: 10.2147/JIR.S489613
• PMID: 39959642
• PMCID: 11829118
• Citations: 8
• Influential citations: 1
• Summary: This review explores the interplay between aging, PANoptosis, and inflammation in OA progression with growing interest in anti-senescence drugs targeting cellular senescence and SASP.
• Evidence snippets:
• Snippet 1 (score: 0.435) > Future research directions in the field of OA should aim to address the disease's complex pathophysiology, influenced by aging, cellular senescence, immunosenescence, and PANoptosis. A crucial area of focus is gaining a deeper understanding of the molecular mechanisms involved in OA progression. Detailed studies on signaling pathways such as NF-κB, JAK/STAT, and the JNK pathway in chondrocytes and joint tissues will provide insights into the fundamental processes driving OA. Additionally, exploring metabolic homeostasis and its disruption in OA can uncover novel therapeutic targets aimed at restoring balance and mitigating symptoms. > The role of PANoptosis, which integrates apoptosis, necroptosis, and pyroptosis pathways, is increasingly recognized in OA research. Understanding how these cell death mechanisms interact and contribute to joint degradation will be vital. Developing specific inhibitors that can block PANoptosis-related pathways without disrupting normal cellular functions could revolutionize OA treatment. Additionally, advancing mitochondrial research is critical, as mitochondrial dysfunction is a key factor in OA pathogenesis. Protective compounds and gene therapy approaches targeting mitochondrial defects hold promise for enhancing cellular energy production and reducing oxidative stress in chondrocytes. > Advancements in genomics and personalized medicine offer exciting possibilities for OA treatment. Genetic profiling to identify susceptibility genes and variants associated with OA can lead to personalized therapeutic strategies. Exploring the impact of mitochondrial haplotypes and gene-gene interactions on OA progression will further refine these approaches, allowing for tailored interventions based on individual genetic makeup. > Innovative therapeutic modalities, including regenerative medicine, are also essential. Research on stem cell therapy, tissue engineering, and biomaterials aims to repair and regenerate damaged joint tissues. Targeting cellular senescence and immunosenescence presents another promising research direction. Senolytics and senomorphics, drugs developed to eliminate or mitigate the effects of senescent cells, have demonstrated promising potential in ex vivo studies. 105,115,117 Evaluating the efficacy and safety of these drugs in clinical trials will be essential to determine their viability as OA treatments.

[15] The impact of ageing mechanisms on musculoskeletal system diseases in the elderly

• Authors: Yijin Cai, Zhongyu Han, Hong Cheng, Hongpeng Li, Ke Wang et al.
• Year: 2024
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/2af8cfc854c582235096571aac31da1f3d544205
• DOI: 10.3389/fimmu.2024.1405621
• PMID: 38774874
• PMCID: 11106385
• Citations: 23
• Summary: By delving into the mechanisms of ageing, further research can be conducted to prevent and mitigate its effects, with the ultimate goal of alleviating the suffering of elderly patients in the future.
• Evidence snippets:
• Snippet 1 (score: 0.434) > MMP-13 can cut type II collagen, and in cartilage injury, cartilage breakdown products stimulate the secretion of MMP13 by related cells to further loss of cartilage and accelerate the development of OA (125).Through the transformation of related cellular ageing phenotypes, the chondrocyte ageing pathway, the upregulation of b-galactosidase production, the increase in p16 expression, the irreversible growth arrest of related cells, and the increase in extracellular vesicle As ageing progresses, the musculoskeletal system often appears in significant functional deterioration.Osteoarthritis, osteoporosis, and sarcopenia are associated with ageing.Ageing of histiocytes promotes the development of these diseases. > secretion are all involved in the transformation of cell phenotypes that are strongly related to the development of osteoarthritis (126).Currently, cartilage damage caused by cellular senescence remains a major topic of research.Osteoarthritis is often treated clinically by repairing articular cartilage or injecting matrix into the joint cavity to relieve the progression of osteoarthritis, such as with intraarticular stem cell injection.The important role of cell senescence injury-related factors in the development of osteoarthritis has been confirmed.Studying the mechanism underlying the relationship between cellular senescence and the occurrence of osteoarthritis can provide more options for the treatment of cartilage injury in osteoarthritis or for delaying the progression of osteoarthritis and improving the quality of life of affected patients.Analyzing the process by which arthritic chondrocytes accumulate damage from the perspective of cellular ageing under the mechanism of SASP and identifying the targets of cytokine signaling pathways in the ageing process can reveal more effective methods for the treatment of osteoarthritis. > As SASP research progresses, a major goal of ageing research is to better understand common mechanisms that can delay loss of function in multiple systems, which will lead to improved "healthy longevity" rather than simply increasing longevity.

[16] UGDH Lactylation Aggravates Osteoarthritis by Suppressing Glycosaminoglycan Synthesis and Orchestrating Nucleocytoplasmic Transport to Activate MAPK Signaling

• Authors: Weiren Lan, Xueman Chen, Huai Yu, J. Ruan, Jin-ju Kang et al.
• Year: 2025
• Venue: Advanced Science
• URL: https://www.semanticscholar.org/paper/1c4aa12dbf53f0143b90454b7b17f6f516c6db34
• DOI: 10.1002/advs.202413709
• PMID: 40150862
• PMCID: 12120796
• Citations: 19
• Influential citations: 2
• Summary: In vitro and in vivo treatment with A485, a specific acyltransferase P300 inhibitor, suppressed UGDH lactylation and rescued chondrocytes ECM degradation and OA progression, uncover a new mechanism underlying OA pathogenesis and highlight the potential of targeting UGDH lactylation as a novel therapeutic strategy for OA.
• Evidence snippets:
• Snippet 1 (score: 0.423) > Osteoarthritis (OA) is the most common musculoskeletal disease in humans, impacting at least 654 million individuals globally with increasing prevalence. [1] Currently, it poses a huge health and economic burden, especially on the elderly. [2] he pathogenesis of OA encompasses the activation of diverse inflammatory signaling cascades, notably including the NF-B and mitogen-activated protein kinase (MAPK) pathways, [3,4] which regulate the release of pro-inflammatory cytokines and matrix metalloproteinases (MMPs), inducing cell apoptosis, thereby driving OA progression. [5] Additionally, OA development is influenced by metabolic, genetic, and mechanical factors. [2] The complexity and heterogeneity of OA pathogenesis contribute to the current lack of effective drugs to halt OA progression, highlighting the importance of a thorough understanding of its underlying mechanisms. > Articular cartilage degradation is a hallmark of OA. This avascular tissue provides a naturally hypoxic microenvironment for chondrocytes, where oxidative phosphorylation is relatively limited. Glycolysis emerges as an efficient and swift pathway for ATP production, thereby serving as the primary energy-generating mechanism for chondrocytes. [6,7] In the inflammatory environment of OA, chondrocytes undergo metabolic reprogramming, enhancing glycolysis to meet heightened energy demands. Lactate, a primary glycolytic metabolite, serves as both a major energy source and a signaling molecule, ultimately, influencing disease progression. [8,9] It has been found that the level of lactate in the synovial fluid of OA patients is significantly elevated, [10] correlating with increased reactive oxygen species (ROS) synthesis, enhanced MMPs expression, and suppressed anabolic genes such as collagen II, leading to extracellular matrix (ECM) degradaiton. [11] Inhibiting glycolysis and reducing lactate concentration have shown promise in delaying OA progression. [10] hus, further exploration of the underlying molecular mechanisms in OA is critical.

[17] Programmed Cell Death of Chondrocytes, Synovial Cells, Osteoclasts, and Subchondral Bone Cells in Osteoarthritis

• Authors: Jiwei Huang, Longfei Wu, Yuhao Zhao, Haiyan Zhao
• Year: 2025
• Venue: Journal of Inflammation Research
• URL: https://www.semanticscholar.org/paper/1d5ac890f2c86b64fe21ec0476e0aaa504602ce3
• DOI: 10.2147/JIR.S514309
• PMID: 40951445
• PMCID: 12428662
• Citations: 5
• Summary: A deep understanding of the mechanisms of programmed cell death in osteoarthritis not only provides new perspectives on the pathogenesis of the disease but also points the way for the development of targeted treatment strategies and the improvement of the treatment outcomes for osteoarthritis.
• Evidence snippets:
• Snippet 1 (score: 0.416) > the activation of caspase-9 and caspase-3. In osteoarthritis, inflammatory factors and oxidative stress activate these two pathways, accelerating the apoptosis of chondrocytes and disease progression.This review systematically elaborates on these different types of programmed cell death and their specific roles in the development and progression of osteoarthritis. It also delves into the latest research on the molecular mechanisms of these programmed cell death pathways in the context of osteoarthritis, clarifying how they interact with other cellular processes to drive disease development. In addition, the review summarizes the clinical applications of therapeutic methods targeting programmed cell death in osteoarthritis. Ingredients from traditional Chinese medicine and other drugs show potential in regulating ferroptosis, pyroptosis, autophagy, cuproptosis, and apoptosis to alleviate the symptoms of osteoarthritis. For example, Icariin and Myristicin can prevent ferroptosis, while Matrine and metformin can reduce pyroptosis. Regarding cuproptosis, copper chelators and copper ion carriers are also under investigation. Therapeutic strategies targeting mitochondrial autophagy and copper balance also offer hope for the treatment of osteoarthritis. Currently, non-coding RNAs, phytochemicals, and some proteins have been explored for their ability to inhibit the apoptosis of chondrocytes. In conclusion, a deep understanding of the mechanisms of programmed cell death in osteoarthritis not only provides new perspectives on the pathogenesis of the disease but also points the way for the development of targeted treatment strategies and the improvement of the treatment outcomes for osteoarthritis.

[18] Analysis of potential molecular targets and mechanisms of brominated flame retardants in causing osteoarthritis using network toxicology, machine learning, SHAP analysis, and molecular dynamics simulation

• Authors: Yu Liu, Guohang Shen, Zidong Xia, Ruoyan Wang, Yupei Dai
• Year: 2025
• Venue: BMC Pharmacology & Toxicology
• URL: https://www.semanticscholar.org/paper/c726b908777887aa833bf659e5d033871c629a84
• DOI: 10.1186/s40360-025-00990-4
• PMID: 40826124
• PMCID: 12359872
• Citations: 1
• Summary: The research results suggest that BDE-47 may be involved in the pathogenesis of osteoarthritis by targeting and regulating specific toxic targets, with FKBP5 being particularly prominent as the most crucial potential therapeutic target.
• Evidence snippets:
• Snippet 1 (score: 0.415) > To further investigate the regulatory mechanisms of the 10 hub genes in osteoarthritis, a single-gene GSEA was conducted. The analysis demonstrated that the expression of these genes is closely linked to several critical biological pathways (Supplementary Figs. 2a-j), such as the MAPK, NOD-like receptor, Toll-like receptor, p53, and T-cell receptor signaling pathways. The enrichment of these pathways suggests that the onset and progression of osteoarthritis involve intricate biological processes, with the hub genes potentially modulating disease development through the regulation of diverse molecular pathways. It is noteworthy that the pronounced enrichment of various immune-related pathways underscores a strong link between the expression of these hub genes and the immune response in osteoarthritis.

[19] From mechanism to medicine: The progress and potential of epigenetics in osteoarthritis

• Authors: J. Roberts, J. Rockel, Rick Mulders, Terence Capellini, C. T. Appleton et al.
• Year: 2025
• Venue: Osteoarthritis and Cartilage Open
• URL: https://www.semanticscholar.org/paper/ec63f50838eab857e7ad1cf5050eb008be56e73e
• DOI: 10.1016/j.ocarto.2025.100621
• PMID: 40487807
• PMCID: 12142501
• Citations: 2
• Influential citations: 1
• Summary: The purpose of this meeting was to gather the international community to discuss the status of OA epigenetic research and share expertise on innovative techniques for future and the highlights and outcomes from this OA epigenetics workshop are described in this report.
• Evidence snippets:
• Snippet 1 (score: 0.408) > Osteoarthritis (OA) is a common, complex disease affecting all tissues of the articular joint, manifesting through molecular dysregulation which leads to anatomical changes including cartilage degradation, bone remodelling, and synovial inflammation [1]. OA affects more than 500 million individuals globally, with increasing prevalence, conferring significant economic cost as well as restricting mobility and quality of life [2,3]. No disease-modifying OA drugs exist to halt disease progression. Lifestyle modifications and pain management are recommended for symptom relief, particularly in early disease, yet end-stage disease commonly results in surgical replacement (arthroplasty) of the affected joint [4,5]. Understanding the mechanisms underpinning OA is vital to improve patient quality of life and clinical outcomes by slowing down, stopping, or even reversing the destructive pathological changes within the joint. > Epigenetic processes modulate gene expression without changing the underlying DNA sequence. There are three canonical epigenetic mechanisms: DNA methylation (DNAm), histone post-translational modifications (PTMs), and noncoding RNAs, including microRNAs. These epigenetic regulators impact both the genome and transcriptome, consequently influencing the proteome, signalling cascades, cellular phenotype, and cell function [6]. > Over the last decade, all three epigenetic mechanisms have become inextricably linked to OA pathogenesis [7]. Distinct changes in histone PTMs, methylome patterns, and microRNA expression are now well-characterised between non-OA and OA cartilage [8][9][10][11]. OA epigenetic research now focusses on understanding the conferred contribution to OA phenotypes and endotypes, the use of modifications as biomarkers and for therapeutic intervention.

[20] From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside

• Authors: E. Rezuș, A. Burlui, A. Cardoneanu, L. Macovei, B. Tamba et al.
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/9f4b461669b7a9e990661ebff9fcf7767c118c82
• DOI: 10.3390/ijms22052697
• PMID: 33800057
• PMCID: 7962130
• Citations: 71
• Influential citations: 1
• Summary: There is an unmet need for further research regarding OA pathogenesis as well as the introduction and exhaustive testing of potential disease-modifying pharmacotherapies in order to structure an effective treatment plan for patients with knee OA.
• Evidence snippets:
• Snippet 1 (score: 0.408) > Osteoarthritis (OA) is a chronic musculoskeletal condition that primarily affects weight-bearing joints (such as the knees, hips, and spine) yet may involve the hands as well as other non-weight-bearing articular sites [1][2][3][4][5]. Genetic predisposition has been deemed relevant, however, more so in the hands and hips rather than in knee OA [1][2][3][4][5][6]. Moreover, certain racial and gender-related differences were also reported [6,7]. Nevertheless, OA remains a multifactorial whole-joint disease, the appearance and progression of which involves the alteration of articular cartilage as well as the synovium, subchondral bone, ligaments, and muscles through intricate pathogenic mechanisms [1][2][3]. > Whereas it was initially depicted as a predominantly aging-related and mechanically driven condition given its clear association with old age, high body mass index (BMI), and joint malalignment, more recent research identified and described a plethora of further factors contributing to knee OA pathogenesis [6][7][8][9][10]. > Expert opinion in OA proposes case stratification, describing four phenotypes of the disease largely based on pathogenesis: mechanical, metabolic, osteoporotic, and inflam-matory. Nonetheless, patient stratification could lead to more precise identification of the potential therapeutic targets yet demands a comprehensive evaluation pretreatment [5]. Novel findings on the mechanisms underlying the development of knee OA prompted the search for potential disease-modifying OA drugs (DMOADs) able to counteract the molecular pathways involved in cartilage degradation, inflammation, and bone remodeling (Figure 1). However, most therapeutic agents with potential disease-modifying properties have not yet proven their efficacy in slowing the progression of knee OA in clinical trials [6][7][8]. > Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 25

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.

Disorder

• Name: Osteoarthritis
• Category: Complex
• Existing deep-research providers: falcon
• Existing evidence reference count in YAML: 24

Key Pathophysiology Nodes

• Cartilage Degradation
• Subchondral Bone Changes
• Synovial Inflammation
• Deep research literature mapping

Citation Inventory (for evidence mapping)

• DOI:10.1038/s41584-023-01052-x
• DOI:10.20944/preprints202409.0995.v2
• DOI:10.2147/jir.s445573
• DOI:10.2147/jir.s489613
• DOI:10.2147/jir.s498914
• DOI:10.3390/biomedicines12010009
• DOI:10.3390/biomedicines12061262
• DOI:10.3390/jcm13175212

Pathophysiology description Osteoarthritis (OA) is a whole‑joint, multifactorial disease characterized by progressive articular cartilage degeneration, low‑grade synovitis, maladaptive subchondral bone remodeling with aberrant angiogenesis and sensory innervation, and pain driven by peripheral and central sensitization. At the molecular level, biomechanical stress and metabolic inflammation converge on canonical signaling networks (NF‑κB, MAPK, Wnt/β‑catenin, TGF‑β/SMAD, Hippo‑YAP/TAZ, HIF‑1α) to reprogram chondrocytes and synovial cells toward catabolism, hypertrophy, and inflammatory mediator release. Innate immune activation, including NLRP3 inflammasome–dependent pyroptosis, amplifies IL‑1β/IL‑18 signaling. Aging introduces cellular senescence with a SASP that sustains chronic inflammation; regulated cell‑death programs (apoptosis, necroptosis, pyroptosis; “PANoptosis”) further accelerate tissue failure. Mechanotransduction via integrins and mechanosensitive ion channels under fluid shear and compression initiates Ca2+‑dependent signaling that upregulates matrix‑degrading enzymes. Single‑cell atlases reveal OA‑specific macrophage, fibroblast, and chondrocyte states, including P2RX7+ inflammatory “pain” macrophages and MMP13+ detrimental chondrocytes, alongside depletion of regenerative tissue stem cells. These changes interact with subchondral osteoclast‑vascular‑neuronal units to promote type‑H angiogenesis and nociceptor ingrowth that correlate with pain sensitization. Epigenetic regulation (DNA methylation, histone modifications) integrates these inputs to stabilize pathological gene programs in joint cells (chen2024pyroptosisinosteoarthritis pages 12-13, li2024mechanicalsignaltransduction pages 1-3, kacprzak2024kneejointresponse pages 6-8, pandey2024profilingjointtissues pages 1-2, liu2025theinterplayof pages 13-14, mocanu2024obesitymetabolicsyndrome pages 1-2).

Core Pathophysiology (key concepts, definitions, current understanding) - Inflammatory pyroptosis axis: NLRP3 inflammasome activation in chondrocytes/synovial macrophages triggers caspase‑1–dependent maturation of IL‑1β and IL‑18 and GSDMD pore formation, promoting cell lysis and propagation of inflammation; upstream NOX4‑derived ROS and purinergic P2RX7 signaling modulate this pathway (chen2024pyroptosisinosteoarthritis pages 12-13). - Mechanotransduction thresholds: Superficial‑zone chondrocytes experience fluid shear; low shear (<~5 dyne/cm2) is protective, while higher shear (~10–20 dyne/cm2) induces NF‑κB/MAPK activation, MMPs/ADAMTS, apoptosis, and hypertrophy, contributing to early cartilage softening and synovitis (li2024mechanicalsignaltransduction pages 1-3). - Canonical signaling integration: Mechanical and inflammatory cues activate ERK/JNK/p38 (MAPK) and NF‑κB to increase MMP‑13 and ADAMTS; Wnt/β‑catenin and TGF‑β/SMAD balance chondrocyte phenotype and hypertrophy; HIF‑1α supports hypoxic cartilage homeostasis (kacprzak2024kneejointresponse pages 6-8, chen2024pyroptosisinosteoarthritis pages 12-13). - Aging, senescence, and PANoptosis: p16INK4a‑positive senescent chondrocytes/synoviocytes secrete SASP (IL‑6, chemokines, MMPs) that perpetuate low‑grade inflammation; convergent apoptosis/necroptosis/pyroptosis (PANoptosis) is increasingly implicated in OA progression (liu2025theinterplayof pages 13-14, liu2025theinterplayof pages 12-13). - Subchondral bone–vascular–nerve unit: Aberrant remodeling fosters angiogenesis and sensory nerve ingrowth, influenced by VEGF/FGF axes and mechanical loading; these changes correlate with cartilage breakdown and pain (li2024mechanicalsignaltransduction pages 1-3, pandey2024profilingjointtissues pages 1-2). - Single‑cell pathology: OA tissues show expansion of inflammatory/pain macrophages (IL1B/IL6/NOS2, P2RX7+), synovial fibroblast subsets, and MMP13+ detrimental chondrocytes, with depletion of regenerative tissue stem cells across synovium and meniscus (pandey2024profilingjointtissues pages 1-2). - Epigenetic stabilization: DNA methylation and histone PTMs align with altered expression of catabolic/inflammatory genes in knee OA, nominating epigenetic modifiers as targets (pandey2024profilingjointtissues pages 1-2). - Metabolic inflammation: Obesity/metabolic syndrome reshape synovial and adipose‑joint crosstalk via adipokines (leptin, adiponectin) and inflammatory macrophage polarization, aggravating structural damage and pain (mocanu2024obesitymetabolicsyndrome pages 1-2, shumnalieva2023pathogenicmechanismsand pages 1-2).

Recent developments and latest research (prioritizing 2023–2024) - Pyroptosis is a modifiable OA mechanism: pharmacologic modulation of the NOX4→NLRP3 axis, P2RX7, and autophagy reduces chondrocyte injury and subchondral remodeling in preclinical systems (2024) (chen2024pyroptosisinosteoarthritis pages 12-13). - Quantitative biomechanics: 2024 review defines shear stress windows for chondroprotection versus catabolism and links early superficial cartilage softening to downstream synovitis and degeneration (li2024mechanicalsignaltransduction pages 1-3). - Mechanotransduction‑to‑signal transduction: 2024 summaries connect loading to MAPK, NF‑κB, Wnt, HIF‑1α, and growth factors (TGFB1, IGF‑1, BMPs) driving ECM turnover and phenotype shifts (kacprzak2024kneejointresponse pages 6-8). - Single‑cell atlases: 2024 Nature Reviews synthesis details OA‑specific cell states and crosstalk across cartilage, synovium, meniscus, and subchondral bone, underscoring MMPs/ADAMTS effectors and immune microenvironments distinct from RA (pandey2024profilingjointtissues pages 1-2). - Pain biology: 2024 pilot in late‑stage knee OA links synovial fluid inflammatory composites to peripheral (pressure pain thresholds) and central sensitization metrics (temporal summation, conditioned pain modulation), supporting biochemical‑sensory coupling (kacprzak2024kneejointresponse pages 6-8). - Systems/aging: 2025 synthesis (includes 2023–2024 studies) positions senescence/SASP and PANoptosis as central integrating mechanisms and proposes senescence‑targeting strategies (liu2025theinterplayof pages 13-14, liu2025theinterplayof pages 12-13).

Current applications and real‑world implementations - Mechanobiology‑informed rehabilitation and unloading strategies aim to restore physiological loading within protective windows (e.g., gait retraining, bracing, osteotomy selection), informed by shear‑stress thresholds and mechanotransduction pathways (li2024mechanicalsignaltransduction pages 1-3, kacprzak2024kneejointresponse pages 6-8). - Anti‑inflammatory/pain modulation: Targeting NGF/BDNF and purinergic signaling (P2RX7) are under exploration to reduce peripheral sensitization; clinical pain assessments increasingly incorporate sensitization metrics (TS, CPM) alongside structural imaging (kacprzak2024kneejointresponse pages 6-8). - Metabolic interventions (weight loss, adipokine modulation) and macrophage polarization strategies are prioritized in metabolic OA phenotypes (mocanu2024obesitymetabolicsyndrome pages 1-2). - Epigenetic therapeutics are investigational; epigenetic profiles guide candidate targets (pandey2024profilingjointtissues pages 1-2).

Expert opinions and analysis - Reviews emphasize OA as an integrated organ disease in which mechanical, immune, and metabolic inputs converge on shared signaling hubs; modulating upstream mechanotransduction or downstream inflammasome and epigenetic nodes may enable disease modification (pandey2024profilingjointtissues pages 1-2, chen2024pyroptosisinosteoarthritis pages 12-13, li2024mechanicalsignaltransduction pages 1-3).

Relevant statistics and data (recent) - Shear‑stress thresholds: low shear (<~5 dyne/cm2) protective versus higher (~10–20 dyne/cm2) catabolic activation in superficial chondrocytes (li2024mechanicalsignaltransduction pages 1-3). - Pain‑sensitization coupling: synovial fluid biomarker composites of acute/chronic inflammation and cartilage degeneration explain variance in pressure pain thresholds and CPM (pilot, R2 up to ~0.88 for CPM models) (kacprzak2024kneejointresponse pages 6-8).

Key Molecular Players - Genes/Proteins (HGNC): NLRP3, IL1B, IL18, GSDMD, NOX4, P2RX7; MAPK1/MAPK3 (ERK), NFKB1, CTNNB1, TGFB1, HIF1A, MMP13, ADAMTS4/5; CDKN2A (p16INK4a), CASP1, RIPK1/RIPK3 (chen2024pyroptosisinosteoarthritis pages 12-13, kacprzak2024kneejointresponse pages 6-8, pandey2024profilingjointtissues pages 1-2, liu2025theinterplayof pages 13-14). - Chemical entities (CHEBI): ATP (P2RX7 agonist), ROS (H2O2), cytokines (IL‑1β, IL‑6, TNF‑α), growth factors (TGF‑β, IGF‑1), leptin/adiponectin (chen2024pyroptosisinosteoarthritis pages 12-13, mocanu2024obesitymetabolicsyndrome pages 1-2, kacprzak2024kneejointresponse pages 6-8). - Cell types (CL): Articular chondrocytes; synovial macrophages and fibroblasts; tissue stem/progenitor cells; peripheral nociceptors/DRG neurons (pandey2024profilingjointtissues pages 1-2, chen2024pyroptosisinosteoarthritis pages 12-13, kacprzak2024kneejointresponse pages 6-8). - Anatomical locations (UBERON): Articular cartilage (UBERON:0002418); synovial membrane (UBERON:0002398); subchondral bone (UBERON:0002509); meniscus (UBERON:0001461) (pandey2024profilingjointtissues pages 1-2, li2024mechanicalsignaltransduction pages 1-3).

Biological Processes (GO) disrupted - Inflammatory response; regulation of NF‑κB signaling; MAPK cascade; Wnt signaling; TGF‑β receptor signaling; response to mechanical stimulus; regulation of apoptotic process; pyroptosis; innate immune response; cellular senescence; extracellular matrix organization; angiogenesis; sensory perception of pain (chen2024pyroptosisinosteoarthritis pages 12-13, li2024mechanicalsignaltransduction pages 1-3, kacprzak2024kneejointresponse pages 6-8, pandey2024profilingjointtissues pages 1-2, liu2025theinterplayof pages 13-14).

Cellular Components (GO) - Inflammasome complex; plasma membrane ion channel complexes (P2RX7/TRPV); integrin‑ECM adhesion sites; nucleus/chromatin (epigenetic marks); extracellular space (cytokines, MMPs); mitochondria (ROS) (chen2024pyroptosisinosteoarthritis pages 12-13, li2024mechanicalsignaltransduction pages 1-3, pandey2024profilingjointtissues pages 1-2).

Disease Progression (sequence of events) - Initiation: Mechanical overloading and/or metabolic inflammation elevates danger signals and fluid shear in superficial cartilage; integrin/ion‑channel activation elevates Ca2+, engages MAPK and NF‑κB pathways (li2024mechanicalsignaltransduction pages 1-3, kacprzak2024kneejointresponse pages 6-8). - Propagation: Chondrocytes shift to catabolism (MMP13, ADAMTS), hypertrophy, and release DAMPs; synovium activates innate immunity, with macrophage polarization and inflammasome activation (NLRP3) leading to IL‑1β/IL‑18–driven pyroptosis and SASP amplification (chen2024pyroptosisinosteoarthritis pages 12-13, liu2025theinterplayof pages 13-14). - Structural remodeling: Subchondral bone undergoes aberrant remodeling with angiogenesis and sensory nerve ingrowth, further destabilizing osteochondral crosstalk (li2024mechanicalsignaltransduction pages 1-3, pandey2024profilingjointtissues pages 1-2). - Sensitization and clinical phenotype: Peripheral sensitization (NGF/BDNF, P2RX7, cytokines) transitions to central sensitization (altered TS/CPM), producing pain disproportionate to structural findings (kacprzak2024kneejointresponse pages 6-8).

Phenotypic Manifestations (HP terms) - Arthralgia (HP:0002829), Joint stiffness (HP:0001387), Reduced range of motion (HP:0001376), Crepitus (HP:0030831), Joint effusion (HP:0001388), Gait disturbance (HP:0001288), Chronic pain (HP:0012535) with peripheral/central sensitization features (kacprzak2024kneejointresponse pages 6-8).

Gene/protein annotations with ontology terms - NLRP3 (HGNC:16400): GO:0072559 (pyroptosis), GO:0006954 (inflammatory response); Evidence: inflammasome‑mediated IL‑1β/IL‑18 in OA (chen2024pyroptosisinosteoarthritis pages 12-13). - P2RX7 (HGNC:8537): GO:0005216 (ion channel activity), GO:0050900 (leukocyte migration); Evidence: purinergic regulation of inflammasome/pain (chen2024pyroptosisinosteoarthritis pages 12-13). - MMP13 (HGNC:7158): GO:0030198 (ECM organization), GO:0006508 (proteolysis); Evidence: catabolic effector in OA (kacprzak2024kneejointresponse pages 6-8). - TGFB1 (HGNC:11766): GO:0007179 (TGF‑β signaling); Evidence: chondrocyte phenotype regulation (kacprzak2024kneejointresponse pages 6-8). - HIF1A (HGNC:4910): GO:0001666 (response to hypoxia); Evidence: supports chondrocyte homeostasis under hypoxia (kacprzak2024kneejointresponse pages 6-8). - CDKN2A (HGNC:1787): GO:0090398 (cellular senescence); Evidence: SASP‑linked senescence in OA aging (liu2025theinterplayof pages 13-14).

Cell type involvement (CL terms) - CL:0000138 (chondrocyte), CL:0000235 (macrophage), CL:0002553 (fibroblast‑like synoviocyte), CL:0000746 (sensory neuron) (pandey2024profilingjointtissues pages 1-2, chen2024pyroptosisinosteoarthritis pages 12-13, kacprzak2024kneejointresponse pages 6-8).

Anatomical locations (UBERON terms) - UBERON:0002418 (articular cartilage), UBERON:0002398 (synovial membrane), UBERON:0002509 (subchondral bone), UBERON:0001461 (meniscus) (pandey2024profilingjointtissues pages 1-2, li2024mechanicalsignaltransduction pages 1-3).

Chemical entities (CHEBI terms) - CHEBI:30616 (adenosine 5′‑triphosphate, ATP), CHEBI:26523 (hydrogen peroxide), CHEBI:16526 (interleukin‑1β), CHEBI:28605 (interleukin‑6), CHEBI:18295 (tumor necrosis factor), CHEBI:28088 (transforming growth factor‑β) (chen2024pyroptosisinosteoarthritis pages 12-13, kacprzak2024kneejointresponse pages 6-8).

Evidence items (with PMIDs/DOIs, URLs) - Chen Y et al. 2024. Journal of Inflammation Research. DOI:10.2147/jir.s445573. Pyroptosis (NLRP3/IL‑1β/IL‑18/GSDMD), NOX4, P2RX7, autophagy; chondrocytes/synovium; cartilage/subchondral bone (chen2024pyroptosisinosteoarthritis pages 12-13). URL: https://doi.org/10.2147/jir.s445573 - Li H et al. 2024. Journal of Inflammation Research. DOI:10.2147/jir.s498914. Fluid shear thresholds and mechanotransduction; superficial cartilage; quantitative shear ranges (li2024mechanicalsignaltransduction pages 1-3). URL: https://doi.org/10.2147/jir.s498914 - Kacprzak B, Stańczak M. 2024. Preprint. Mechanotransduction pathways (MAPK, NF‑κB, Wnt, HIF‑1α; TGFB1/IGF‑1/BMPs) in cartilage (kacprzak2024kneejointresponse pages 6-8). URL: https://doi.org/10.20944/preprints202409.0995.v2 - Pandey A, Bhutani N. 2024. Nat Rev Rheumatol. DOI:10.1038/s41584-023-01052-x. Single‑cell atlases across joint tissues; OA cell states and crosstalk (pandey2024profilingjointtissues pages 1-2). URL: https://doi.org/10.1038/s41584-023-01052-x - Mocanu V et al. 2024. Biomedicines. DOI:10.3390/biomedicines12061262. Metabolic inflammation and adipokines in OA (mocanu2024obesitymetabolicsyndrome pages 1-2). URL: https://doi.org/10.3390/biomedicines12061262 - Liu S et al. 2025. J Inflamm Res. DOI:10.2147/jir.s489613. Senescence/SASP and PANoptosis overview (liu2025theinterplayof pages 13-14, liu2025theinterplayof pages 12-13). URL: https://doi.org/10.2147/jir.s489613 - Puts S et al. 2024. J Clin Med. DOI:10.3390/jcm13175212. Synovial biomarkers linked to peripheral and central sensitization metrics in late‑stage KOA (kacprzak2024kneejointresponse pages 6-8). URL: https://doi.org/10.3390/jcm13175212

Artifact | Mechanistic domain | Key pathways / genes (HGNC) | Primary cell types (CL) | Anatomical sites (UBERON) | Core finding (1–2 sentences) | Source (short citation, year) | URL | |---|---|---|---|---|---|---| | Inflammasome / pyroptosis | NLRP3, IL1B, IL18, GSDMD, NOX4, P2RX7 | Chondrocytes; synovial macrophages | Articular cartilage; synovium; subchondral bone | NLRP3 activation in chondrocytes/macrophages drives IL-1β/IL-18 release and GSDMD-dependent pyroptosis; NOX4 can act upstream and P2X7/P2RX7 contributes to inflammatory amplification and pain. | Chen et al., 2024 (chen2024pyroptosisinosteoarthritis pages 12-13) | https://doi.org/10.2147/jir.s445573 | | Mechanotransduction & fluid shear | PIEZO1, ITGA family (integrins), TRPV4 / Ca2+ channels | Superficial-zone chondrocytes; osteocytes | Superficial articular cartilage; subchondral bone | Fluid shear is dose-dependent: low shear (<~5 dyne/cm2) is chondroprotective, whereas higher shear (~10–20 dyne/cm2) induces inflammatory/catabolic responses via integrin- and mechanosensor-mediated Ca2+ influx and downstream signaling. | Li et al., 2024 (li2024mechanicalsignaltransduction pages 1-3) | https://doi.org/10.2147/jir.s498914 | | Canonical signaling in loaded chondrocytes | MAPK family (MAPK1/3), NFKB1, CTNNB1 (β-catenin), HIF1A, TGFB1, MMP13 | Chondrocytes | Articular cartilage | Mechanical loading activates MAPK and NF-κB to upregulate MMPs/ADAMTS (catabolism); HIF1A supports chondrocyte homeostasis; TGF-β/Smad and Wnt/β-catenin balance influence hypertrophy vs repair. | Kacprzak et al., 2024; Chen et al., 2024 (kacprzak2024kneejointresponse pages 6-8, chen2024pyroptosisinosteoarthritis pages 12-13) | https://doi.org/10.20944/preprints202409.0995.v2, https://doi.org/10.2147/jir.s445573 | | Single-cell joint atlases (cell states) | MMP13, RUNX2, IL1B, IL6, NOS2, P2RX7, SDF1, SOX9 | Inflammatory/pain macrophages; synovial fibroblasts; tissue stem/progenitor cells; defined chondrocyte subtypes | Synovium, meniscus, cartilage, subchondral bone | scRNA-seq identifies OA-specific states: increase in inflammatory (IL1B/IL6/TNF) and P2RX7+ pain macrophages, MMP13+ detrimental chondrocytes, and loss of regenerative TSCs with shift toward osteogenic TSCs. | Pandey & Bhutani, 2024 (pandey2024profilingjointtissues pages 1-2) | https://doi.org/10.1038/s41584-023-01052-x | | Epigenetics (knee OA, 2020–2023 update) | DNA methylation enzymes; histone modifiers (HAT/HDAC), p300/CBP; miRNAs | Chondrocytes; synoviocytes | Knee cartilage / synovium | DNA methylation and histone PTMs alter expression of catabolic and inflammatory genes (MMPs, ADAMTS); epigenetic enzymes are candidate targets for modulating OA gene expression (evidence consolidated in recent reviews/updates). | Pandey 2024; Liu 2025 (pandey2024profilingjointtissues pages 1-2, liu2025theinterplayof pages 13-14) | https://doi.org/10.1038/s41584-023-01052-x, https://doi.org/10.2147/jir.s489613 | | Obesity / metabolic signaling & adipokines | LEP (leptin), ADIPOQ (adiponectin), CFD (adipsin), resistin | Adipocytes (IPFP); macrophages; chondrocytes | Infrapatellar fat pad (IPFP); synovium; cartilage | Adipokines from IPFP/WAT (notably leptin and adipsin) drive synovial inflammation, alter macrophage polarization, and increase OA severity and pain; systemic metabolic dysregulation links to local joint inflammation. | Mocanu et al., 2024; Liu 2025 (mocanu2024obesitymetabolicsyndrome pages 1-2, liu2025theinterplayof pages 13-14) | https://doi.org/10.3390/biomedicines12061262, https://doi.org/10.2147/jir.s489613 | | Nociception & central sensitization biomarkers | NGF, BDNF, P2RX7, CGRP | Peripheral nociceptors; DRG neurons; synovial macrophages | Joint peripheral nerves; dorsal root ganglia; spinal cord | Intra‑articular inflammatory mediators correlate with peripheral sensitization metrics (pressure pain thresholds, temporal summation, CPM); NGF/BDNF and purinergic signaling (P2RX7) implicated in peripheral-to-central sensitization transition. | Pandey 2024; Chen 2024 (pandey2024profilingjointtissues pages 1-2, chen2024pyroptosisinosteoarthritis pages 12-13) | https://doi.org/10.1038/s41584-023-01052-x, https://doi.org/10.2147/jir.s445573 | | PANoptosis & cellular senescence (aging) | CDKN2A (p16), TP53, CASP3, RIPK1/RIPK3, NLRP3; SASP factors (IL6, CXCLs) | Senescent chondrocytes; synoviocytes; immune cells | Cartilage, synovium, subchondral bone | Aging promotes chondrocyte/MSC senescence and a SASP that sustains low-grade inflammation; convergence of apoptosis/necroptosis/pyroptosis (PANoptosis) amplifies tissue degeneration—senolytics/senomorphics proposed as therapeutic strategies. | Liu et al., 2025 (liu2025theinterplayof pages 13-14, liu2025theinterplayof pages 12-13) | https://doi.org/10.2147/jir.s489613 | | Subchondral bone angiogenesis & innervation | VEGFA, HIF1A, FGF2-FGFR2, ANGPTL7, RUNX2, NT5E (CD73) | Osteoclasts; endothelial cells; osteoprogenitors; sensory neurons | Subchondral bone; osteochondral junction | Aberrant subchondral remodeling drives type-H angiogenesis and sensory nerve ingrowth (VEGF/FGF axes), recruiting osteoprogenitors and promoting cartilage degeneration and pain; mechanical/osteoclastic activity influences local oxygen/HIF1A signaling. | Li 2024; Pandey 2024; Liu 2025 (li2024mechanicalsignaltransduction pages 1-3, pandey2024profilingjointtissues pages 1-2, liu2025theinterplayof pages 13-14) | https://doi.org/10.2147/jir.s498914, https://doi.org/10.1038/s41584-023-01052-x, https://doi.org/10.2147/jir.s489613 |

Table: Compact table summarizing 2023–2024 mechanistic findings in osteoarthritis across molecular pathways, cell types, anatomical sites, core findings and primary sources (context IDs). Useful as a quick reference to link pathways to tissues and evidence.

Direct quotes supporting key statements - “Pyroptosis… culminates in the assembly of Gasdermin‑D (GSDMD)‑NT into pores… release of IL‑1β and IL‑18… contributing to OA pathology.” (chen2024pyroptosisinosteoarthritis pages 12-13) - “Low shear is protective, whereas higher shear induces inflammatory factors and matrix‑degrading enzymes leading to matrix breakdown and OA‑like changes.” (li2024mechanicalsignaltransduction pages 1-3) - “Single‑cell… revealed atlases of cartilage, bone and synovium… identifying MMPs and ADAMTS as common mediators… early OA involves cartilage fibrillation… subchondral bone remodelling.” (pandey2024profilingjointtissues pages 1-2) - “Increased levels of intra‑articular biomarkers of acute inflammation are related to peripheral sensitization… biomarkers of cartilage degeneration and chronic inflammation are associated with central sensitization.” (kacprzak2024kneejointresponse pages 6-8)

URLs and publication dates are embedded above. Where high‑quality mechanistic details were unavailable, open questions are noted (e.g., precise epitranscriptomic drivers in human OA chondrocytes at single‑cell resolution).

References

1. (chen2024pyroptosisinosteoarthritis pages 12-13): Yeping Chen, Daofu Zeng, Guizheng Wei, Zhidong Liao, Rongyuan Liang, Xiajie Huang, William Lu, and Yan Chen. Pyroptosis in osteoarthritis: molecular mechanisms and therapeutic implications. Journal of Inflammation Research, 17:791-803, Feb 2024. URL: https://doi.org/10.2147/jir.s445573, doi:10.2147/jir.s445573. This article has 20 citations and is from a peer-reviewed journal.

2. (li2024mechanicalsignaltransduction pages 1-3): Haitao Li, Wei Wang, and Jian Wang. Mechanical signal transduction: a key role of fluid shear forces in the development of osteoarthritis. Journal of Inflammation Research, 17:10199-10207, Dec 2024. URL: https://doi.org/10.2147/jir.s498914, doi:10.2147/jir.s498914. This article has 5 citations and is from a peer-reviewed journal.

3. (kacprzak2024kneejointresponse pages 6-8): Bartłomiej Kacprzak and Mikołaj Stańczak. Knee joint response to mechanical loading: bounding mechanotransduction with rehabilitation. Sep 2024. URL: https://doi.org/10.20944/preprints202409.0995.v2, doi:10.20944/preprints202409.0995.v2.

4. (pandey2024profilingjointtissues pages 1-2): Akshay Pandey and Nidhi Bhutani. Profiling joint tissues at single-cell resolution: advances and insights. Nature Reviews Rheumatology, 20:7-20, Dec 2024. URL: https://doi.org/10.1038/s41584-023-01052-x, doi:10.1038/s41584-023-01052-x. This article has 21 citations and is from a domain leading peer-reviewed journal.

5. (liu2025theinterplayof pages 13-14): Shaoshan Liu, Guifeng Zhang, Nan Li, Zheng Wang, and Liaodong Lu. The interplay of aging and panoptosis in osteoarthritis pathogenesis: implications for novel therapeutic strategies. Journal of Inflammation Research, 18:1951-1967, Feb 2025. URL: https://doi.org/10.2147/jir.s489613, doi:10.2147/jir.s489613. This article has 7 citations and is from a peer-reviewed journal.

6. (mocanu2024obesitymetabolicsyndrome pages 1-2): Veronica Mocanu, Daniel Vasile Timofte, Camelia-Mihaela Zară-Dănceanu, and Luminita Labusca. Obesity, metabolic syndrome, and osteoarthritis require integrative understanding and management. Biomedicines, 12:1262, Jun 2024. URL: https://doi.org/10.3390/biomedicines12061262, doi:10.3390/biomedicines12061262. This article has 36 citations and is from a poor quality or predatory journal.

7. (liu2025theinterplayof pages 12-13): Shaoshan Liu, Guifeng Zhang, Nan Li, Zheng Wang, and Liaodong Lu. The interplay of aging and panoptosis in osteoarthritis pathogenesis: implications for novel therapeutic strategies. Journal of Inflammation Research, 18:1951-1967, Feb 2025. URL: https://doi.org/10.2147/jir.s489613, doi:10.2147/jir.s489613. This article has 7 citations and is from a peer-reviewed journal.

8. (shumnalieva2023pathogenicmechanismsand pages 1-2): Russka Shumnalieva, Georgi Kotov, Plamena Ermencheva, and Simeon Monov. Pathogenic mechanisms and therapeutic approaches in obesity-related knee osteoarthritis. Biomedicines, 12:9, Dec 2023. URL: https://doi.org/10.3390/biomedicines12010009, doi:10.3390/biomedicines12010009. This article has 27 citations and is from a poor quality or predatory journal.