Open research questions in Osteoarthritis Treatment and Mechanisms

What the literature leaves open

• Future AI systems are expected to integrate imaging findings, clinical laboratory biomarkers, wearable sensor data, and molecular information to provide individualized prediction of pain progression and treatment response. Advances in explainable AI, federated learning, and multimodal modeling are likely to improve transparency while maintaining privacy. Successful patient implementation will require collaboration among clinicians, engineers, data scientists, regulators, and patients.

  Artificial Intelligence in Osteoarthritis Pain Management: Current Applications and Future Perspectives · 2026 · DOI

• Major OA-associated matrix-remodeling markers, including MMP-1, MMP-3, and MMP-13, remained largely unchanged, indicating that monoculture conditions are insufficiently sensitive to detect clinically predictive drug-related molecular changes.

  Microfluidic Osteoarthritis-on-a-Chip for Evaluating Joint-Cell Responses to Tanezumab, a Humanized Anti-NGF Monoclonal Antibody · 2026 · DOI

• A major limitation of the current clinical literature is the substantial heterogeneity in PEMF protocols, including differences in carrier and pulse frequencies, field intensities, waveforms, and treatment duration. At present, clinical data supporting disease-modifying effects of PEMF remain insufficient and inconsistent.

  Osteoarthritis: Potential of Pulsed Electromagnetic Field Therapy · 2026 · DOI

• Introduction Osteoarthritis (OA) involves cartilage degradation and subchondral bone alterations, yet the mechanisms of chondro-endothelial crosstalk remain unclear.

  PDGF-BB inhibits SP1/Angptl7 mediated chondro-endothelial crosstalk via stress-sensitivity Piezo1 regulation in osteoarthritis · 2026 · DOI

• High-molecular-weight (HMW) HA (> 1 MDa) is reported to exert anti-inflammatory and matrix-preserving effects; however, its role in multicellular systems remains incompletely understood.

  Effects of high-molecular-weight hyaluronic acid on inflammatory and matrix-associated responses in a chondrocyte–osteoclast co-culture model · 2026 · DOI

• Osteoarthritis (OA) is a degenerative joint disease characterized by progressive disruption of the cartilage extracellular matrix (ECM), yet the molecular mechanisms governing ECM turnover during disease initiation remain incompletely defined.

  TMEM2 regulates hyaluronan turnover and cartilage homeostasis during early osteoarthritis progression · 2026 · DOI

• TCM physical owing therapies, therapeutic massage) and acupoint stimulation, have emerged as promising non- invasive alternatives for the management of musculoskeletal disorders in LFJ OA have not been fully elucidated.

  Therapeutic effect of modified meridian-guided acupoint pressing on lumbar facet joint osteoarthritis: an integrated microbiomics and metabolomics analysis · 2026 · DOI

• In recent years, ferroptosis and immunosenescence have each been recognized as contributors to OA initiation and progression, yet their potential interplay within the osteoimmune microenvironment remains insufficiently integrated.

  Potential crosstalk between ferroptosis and immunosenescence in osteoarthritis: evidence integration and translational insights from the osteoimmune microenvironment · 2026 · DOI

• Manual therapy (MT) has been proposed to modulate pain and improve function; however, its effectiveness in specifically targeting hamstring tightness in KOA remains unclear.

  Effectiveness of manual therapy targeting hamstring tightness in knee osteoarthritis: a systematic review of rehabilitation outcomes · 2026 · DOI

• The main limitations of this study were its singlecenter observational design, absence of a control group, modest sample size, and use of plain radiography for structural assessment. Therefore, causal inference regarding the effect of corticosteroid injection on radiographic progression should be made cautiously.

  The Impact of a Single-Dose Intra-Articular Corticosteroid Injection on Disease Progression and Two-Year Functional Outcomes in Kellgren-Lawrence Grade 1 Knee Osteoarthritis · 2026 · DOI

• However, optimal inhalation parameters and the dose-response relationship between hydrogen inhalation duration and symptomatic relief in KOA patients remain uncertain.

  Effects of hydrogen inhalation duration on symptom relief in elderly patients with knee osteoarthritis: A pilot study · 2026 · DOI

• Objective: Enhanced glycolysis is a metabolic hallmark of chondrocytes in osteoarthritis (OA); however, the roles of the glycolytic rate-limiting enzyme hexokinase 2 (HK2) in cartilage remain poorly understood.

  Inhibition of hexokinase 2 undermines cartilage health and accelerates osteoarthritis · 2026 · DOI

• Background: Autologous adipose-derived stromal vascular fraction (SVF) is increasingly used for symptomatic knee osteoarthritis (OA), but it remains uncertain whether patient age should influence candidacy.

  Patient Age Is Not a Determinant of 12-Month Pain Response After Autologous Adipose-Derived Stromal Vascular Fraction Injection for Knee Osteoarthritis · 2026 · DOI

• Fibroblast growth factor 9 (FGF9) has shown cartilage-protective effects in post-traumatic OA models, but its role in chondrocyte degeneration and OA pathogenesis remains unclear.

  FGF9 attenuates osteoarthritis progression through the NRF2/GPX3 antioxidant axis · 2026 · DOI

• The strengths of this study include its longitudinal design, which enables temporal assessment of smoking cessation effects, and comprehensive outcome multidimensional evaluation integrating patient–reported outcomes, objective functional measures, respiratory indices, and biochemical 1 3European Journal of Applied Physiology biomarkers. This integrative approach provides a more holistic understanding of OA progression and recovery than studies focusing on single domains. The inclusion of NMJ biomarkers (CAF22) provides novel insights into the association between smoking, muscle health, and OA pro- gression. Moreover, validation of smoking status with both self–report and CO breath testing ensured robust group classification, thereby reducing misclassification bias. How- ever, several limitations merit consideration. First, the one– year follow–up, although sufficient to detect functional and biochemical improvements, may be too short to determine long–term structural joint changes such as radiographic joint space narrowing or sustained disease modification. Second, the absence of advanced imaging techniques, such as MRI, or radiographic assessment limits our ability to directly cor- relate biomarker changes with structural joint alterations. Third, the study population was derived from a single cen- ter and included only male participants, which may limit the generalizability of the findings to broader and more diverse populations. Additionally, participant attrition during fol- low–up may have introduced potential bias and reduced statistical power for subgroup analyses. Multicenter, lon- ger–term studies incorporating imaging and broader popu- lations are needed to validate and extend these findings.

  Smoking quitting promotes neuromuscular and cartilage recovery in knee osteoarthritis · 2026 · DOI

• However, the secretome derived from these cells injected in the con- text of TPLO osteotomy healing, remains unexplored, as it exhibits only local activity (Gowen et al.

  Intra-articular injection of allogeneic canine adipose-derived stem cell enriched secretome in dogs undergoing tibial plateau leveling osteotomy: a prospective double-blind and randomized pilot trial · 2026 · DOI

• OA is increasingly recognized as a complex, multifactorial disease that extends beyond mere cartilage degradation to involve the entire joint structure, including subchondral bone, synovium, and surround- ing tissues. Despite significant advancements in our understanding of OA pathophysiology, including the identification of key molecular pathways and genetic factors, considerable gaps remain in elucidating the precise mechanisms underlying disease initiation and progression. The aging population globally, particularly in regions such as China, where projections indicate that nearly 22% of the population will be over 65 by 2033, underscores the urgent need for effective therapeutic strategies to manage OA.1 Currently, there is no approved DMOAD that can halt or reverse the progression of OA. Recent research has discovered various pathways involved in OA, including inflammation, cartilage metabolism, and subchondral bone remodeling. These insights pave the way for the development of novel therapeutic agents that could potentially modify disease progression rather than merely alleviating symptoms. However, the heterogeneity inherent in OA complicates treatment strategies; a one-size-fits-all approach is unlikely to be effective. Instead, there is a growing consensus on the need for personalized medicine approaches that consider individual patient characteristics, including genetic profiles and specific OA phenotypes.

  Novel therapeutic strategies for osteoarthritis: from mechanistic insights to precision medicine · 2026 · DOI

• For example, future research may focus on enhancing early osteoarthritis diagnostics using such state-of-the-art models as Vision Transformers and common convolutional neural networks In addition, combining X-ray images with some clinically-oriented variables, such as age, body mass index, and medical history, may prove helpful.

  Prediction of Knee Osteoarthritis using Hybrid Deep Learning Algorithm · 2026 · DOI

• Our study fills an important gap in our understanding of caspase-8 roles in OA pathophysiology from a molecu- lar and multi-omics perspective, but several key aspects remain unaddressed. Our in vitro experiments and omics analyses primarily focus on primary human OA chondro- cytes, which exhibit substantial donor-to-donor variability compared with standardized small animal models. Conse- quently, the specific molecular interactions within the cas- pase-8–mediated inflammation–senescence–fibrosis axis identified here, require further exploration in controlled in vivo systems, particularly in spontaneous OA models that more accurately recapitulate chronic, low-grade inflamma- tory joint degeneration than post-traumatic models such as ACLT/DMM. Moreover, although we demonstrate path- way-level alterations associated with caspase-8 activity, the precise structural determinants that distinguish its scaffold- ing and catalytic functions in chondrocytes remain unde- fined. Future studies should dissect these domain-specific mechanisms, delineate the isoform-specific roles of cas- pase-8, and identify robust biomarkers reflecting caspase-8 pathway activation in patient samples. Additionally, we plan to incorporate more refined and extended genetic strategies, not only siRNA mediated caspase-8 knockdown but such as knockout via CRISP/Cas9 combined together with rescue experiments, in order to better distinguish the catalytic ver- sus non-catalytic domain-dependent functions of caspase-8 and to strengthen causal inference.

  Multi-omics and experimental evidence in human chondrocytes identify caspase-8 as a non-apoptotic regulator of inflammatory, senescent, and fibrotic signaling in osteoarthritis · 2026 · DOI

• This study has several strengths worth noting. Our sample size (n = 736) includes a predominantly Hispanic/Latino population, a group underrepresented in prior KOA psy- chosocial research. Multiple behavioral determinants were examined concurrently within a single multivariate frame- work rather than in isolation, and all primary outcomes were assessed using validated instruments. Sex-stratified analyses were conducted with standardized effect sizes and 95% confidence intervals reported, and the study adhered to STROBE guidelines for observational research. The study also has some limitations worth noting. The cross-sec- tional design precludes causal inference, and bidirectional relationships cannot be excluded, higher symptom burden may itself reduce self-efficacy and social support rather than the reverse. Additionally, sex comparisons in psychosocial variables were primarily unadjusted, and residual confound- ing by socioeconomic factors cannot be excluded. Assessing related conditions such as kinesiophobia and comorbidities such as depression and anxiety would further allow these factors to be controlled in the analysis and yield greater precision. Lastly, the series of multiple regression models has the potential to increase Type I error. Taken together, a prospective design employing structural equation modeling could be a next logical study to conduct. The wide spectrum of Kellgren–Lawrence grades (0–4) introduces sample heterogeneity. Subgroup analyses com- paring mild-to-moderate (KL grades 0–2, n = 351–352) and moderate-to-severe disease (KL grades 3–4, n = 130–137, varying by variable due to listwise deletion) revealed that associations between psychosocial determinants and symp- tom outcomes were broadly consistent across severity strata (Supplementary Table S1). Patients with higher KL grades reported significantly greater functional limitation (WOMAC; p =.046, d = − 0.21) and more negative affective attitudes toward exercise (p =.005, d = − 0.27), while exercise self-efficacy and other psychosocial variables did not differ significantly between groups. Moderation analyses further indicated that KL grade significantly moderated the associa- tions of social support with VAS (p =.037) and WOMAC (p =.015), and self-efficacy with WOMAC (p =.024), sug- gesting that radiographic severity may amplify select psy- chosocial–symptom relationships in more advanced disease (Supplementary Table S2). These subgroup findings should be interpreted cautiously given the reduced sample sizes in the moderate-to-severe group.

  Sex differences in physical activity, psychosocial determinants, and symptom outcomes in knee osteoarthritis: a cross-sectional analysis of a Hispanic/Latino-predominant cohort · 2026 · DOI

• 162 However, it remains to be further validated whether the ECM formed during this self-assembly process can fully replicate the maturity and structural organization of fully developed native cartilage. A major limitation of current cartilage organoid systems is that they still recapitulate only part of the joint microenvironment.

  Reconstructing intra-articular cell communication networks: Bionic design and research progress of cartilage organoids · 2026 · DOI

• The development of smart responsive biomaterials, allowing the ECM to dynamically respond to changes in the microenvironment and release regulatory signals, is crucial for actively maintaining homeostasis within organoids.

  Reconstructing intra-articular cell communication networks: Bionic design and research progress of cartilage organoids · 2026 · DOI

• (3D) Constructing an in vitro model that reflects the pathological characteristics of OA important for further investigation into the pathological mechanisms of OA. However, the existing two-dimensional cell culture in simulating the complex models have joint structure of human three-dimensional tissues and cellular interactions. This makes it difficult to accurately replicate the dynamic communication between chondrocytes, subchondral bone cells, and immune cells, as well as their integrated responses to inflammatory stimuli, mechanical loading, and metabolic alterations.7 Furthermore, cells cultured in two-dimensional conditions are prone to shifts in cell morphology, phenotypic stability, and gene expression profiles as passage numbers increase, thereby diminishing the model’s representativeness of in vivo pathological states.8 Improvements have been made in spatial support with 3D culture and traditional tissue engineering models; however, limitations exist in reconstructing tissue-layered structures, maintaining cellular heterogeneity, long-term stable culture, and simulating pathological microenvironments such as hypoxia, inflammatory factor concentration gradients, and mechanical stimulation.9 These models are insufficient to fully meet the demands of mechanistic research, drug screening, and translational evaluation. Organoid technology is a novel 3D culture system, providing new possibilities for simulating the structure and function of joint tissues. This technology allows for the self-organization of miniaturized 3D tissues with specific organ structures and functions, offering high physiological relevance and plasticity. It can mimic the complex cellular environments and tissue structures found in vivo, making it useful for disease model development and drug screening. Additionally, organoid technology has strong reproducibility and scalability, making it applicable to research and applications involving various organ types.

  Reconstructing intra-articular cell communication networks: Bionic design and research progress of cartilage organoids · 2026 · DOI

• • This study has provided insights into the transcriptional landscape, signalling networks, cellular metabolic alterations, and gene regulatory networks in the pathogenesis of T2DMOA. intercellular • Although we used four paired samples of articular cartilage and synovium, small sample size of each group still remains a major limitation. • These preliminary fndings warrant further experimental validation to establish their biological and clinical signif- cance.

  The transcriptional atlas, intercellular communication, and metabolic reprogramming of the cartilage and synovium in osteoarthritis patients with diabetes mellitus · 2026 · DOI

• • This study introduced a novel microscope-top loading device with control of oxygen tension during loading and imaging, which allows the interplay of oxygen availability and mechanical loading to be evaluated. This provided interaction efects between novel oxygen tension and mechanical loading. information about • This study is limited by epifuorescence microscopy, which constrains the imaging depth. In addition, future studies should evaluate mechanistic causes of the observed interplay between oxygen tension and mechanical loading. phosphate (NADPH). NADH and NADPH share the same fuorescence spectrum and are labeled NAD(P)H together. FAD and NAD(P)H are vital cofactors in cellular redox reac- tions, and therefore can be used as natural biomarkers of redox balance in cells.13 Fluorescent intensity correlates with accumulation of the corresponding compounds, and optical redox ratio, calculated using FAD and NAD(P)H intensity, is an indicator of redox balance. A previous study from our laboratory showed that ORI metrics can predict mitochondrial membrane potential measured by fuorescent dye in cartilage explants,14 demonstrating the utility of ORI in comparison to established measures of mitochondrial function. Although measurement of autofuorescent signals in cartilage explants is challenging due to other autofuorescent molecules, the bandpass flters used in this study have little overlap with collagen spectra (Supplementary Figure a), therefore they are able to reliably capture intracellular autofuorescence from the targeted cofactors.

  Oxygen tension alters cartilage redox balance in response to traumatic impact · 2026 · DOI

Most-cited papers in Osteoarthritis Treatment and Mechanisms

• Diagnosis and Treatment of Hip and Knee Osteoarthritis · JAMA · 2021 · 2,001 citations
• Clinical Efficacy of the Microfracture Technique for Articular Cartilage Repair in the Knee · The American Journal of Sports Medicine · 2009 · 886 citations
• Prevalence of Symptomatic Hand Osteoarthritis and Its Impact on Functional Status among the Elderly: The Framingham Study · American Journal of Epidemiology · 2002 · 536 citations
• Platelet-Rich Plasma Releasate Inhibits Inflammatory Processes in Osteoarthritic Chondrocytes · The American Journal of Sports Medicine · 2011 · 333 citations
• Ten-Year Follow-up of a Prospective, Randomized Clinical Study of Mosaic Osteochondral Autologous Transplantation Versus Microfracture for the Treatment of Osteochondral Defects in the Knee Joint of Athletes · The American Journal of Sports Medicine · 2012 · 321 citations
• Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture · The American Journal of Sports Medicine · 2014 · 313 citations
• The Pericellular Matrix as a Transducer of Biomechanical and Biochemical Signals in Articular Cartilage · Annals of the New York Academy of Sciences · 2006 · 283 citations
• Structural and Symptomatic Efficacy of Glucosamine and Chondroitin in Knee Osteoarthritis · Archives of Internal Medicine · 2003 · 280 citations
• Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture: Five-Year Follow-up of a Prospective Randomized Trial · The American Journal of Sports Medicine · 2018 · 265 citations
• A Prospective, Single-Blind, Placebo-Controlled Trial of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis · The American Journal of Sports Medicine · 2016 · 262 citations

Most recent work

• Responders vs. non-responders to mesenchymal stromal cells in knee osteoarthritis patients: mechanistic correlates of donor cell attributes and putative patient features · bioRxiv · 2026
• SHAM-PAIN Trial: Genicular Artery Embolization for Reducing Pain in Medically Refractory Symptomatic Knee Osteoarthritis—A Randomized Sham-Controlled Pilot Study · Journal of Vascular and Interventional Radiology · 2026
• CT-based subchondral bone microstructural analysis in knee osteoarthritis via MR-guided distillation learning · Frontiers in Radiology · 2026
• Impact of metformin on the risk of osteoarthritis in patients with type 2 diabetes: a real-world study · Diabetes Research and Clinical Practice · 2026
• Moderate forced running exercise induces cartilage adaptation but exacerbates the molecular cartilage phenotype of type IX collagen knock-out mice · American Journal of Physiology-Cell Physiology · 2026
• Activity-Induced Changes in Pain and Knee Range of Motion in Adults With Knee Osteoarthritis · medRxiv · 2026
• Defining subcellular synovial responses in TMJ osteoarthritis onset via mechanical stress and articular disk derangement models · International Journal of Oral Science · 2026
• Inhibition of PI3K/Akt/mTOR signaling by curcumin: a novel approach to mitigate synovial fibrosis in knee osteoarthritis · The Korean Journal of Physiology & Pharmacology · 2026
• Supervised machine learning model to predict total knee replacement in a large osteoartrhitis real-world evidence dataset using retrospectively 20-year insurance data from Israel · BMC Medical Informatics and Decision Making · 2026
• Prognostic model for osteoarthritis combining imaging and clinical biomarkers · Frontiers in Medicine · 2026

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