Pathophysiology Of Osteoarthritis Research Articles

Editorial introductions.

Editorial introductions.

Microtubule stabilization targeting regenerative chondrocyte cluster for cartilage regeneration.

Purpose: Chondrocytes (CHs) in cartilage undergo several detrimental events during the development of osteoarthritis (OA). However, the mechanism underlying CHs regeneration involved in pathogenesis is largely unknown. The aim of this study was to explore the underlying mechanism of regeneration of CHs involved in the pathological condition and the potential therapeutic strategies of cartilage repair. Methods and Materials: CHs were isolated from human cartilage in different OA stages and the high-resolution cellular architecture of human osteoarthritis was examined by applying single-cell RNA sequencing. The analysis of gene differential expression and gene set enrichment was utilized to reveal the relationship of cartilage regeneration and microtubule stabilization. Microtubule destabilizer (nocodazole) and microtubule stabilizer (docetaxel) treated-human primary CHs and rats cartilage defect model were used to investing the effects and downstream signaling pathway of microtubule stabilization on cartilage regeneration. Results: CHs subpopulations were identified on the basis of their gene markers and the data indicated an imbalance caused by an increase in the degeneration and disruption of CHs regeneration in OA samples. Interestingly, the CHs subpopulation namely CHI3L1+ CHs, was characterized by the cell regenerative capacity, stem cell potency and the activated microtubule (MT) process. Furthermore, the data indicated that MT stabilization was effective in promoting cartilage regeneration in rats with cartilage injury model by inhibiting YAP activity. Conclusion: These findings lead to a new understanding of CHs regeneration in the OA pathophysiology context and suggest that MT stabilization is a promising therapeutic target for OA and cartilage injury.

Joint instability causes catabolic enzyme production in chondrocytes prior to synovial cells in novel non-invasive ACL ruptured mouse model

The Anterior Cruciate Ligament (ACL)-deficient model helps to clarify the mechanism of knee osteoarthritis (OA); however, the conventional ACL injury model could have included concurrent onset factors such as direct compression stress to cartilage and subchondral bone. In this study, we established a novel Non-invasive ACL-Ruptured mouse model without concurrent injuries and elucidated the relationship between OA progression and joint instability. We induced the ACL-Rupture non-invasively in twelve-week-old C57BL/6 male mice and evaluated histological, macroscopical, and morphological analysis at 0 days. Next, we created the ACL-R, controlled abnormal tibial translation (CATT), and Sham groups. Then, the joint stability and OA pathophysiology were analyzed at 2, 4, and 8 weeks. No intra-articular injuries, except for ACL rupture, were observed in the ACL-R model. ACL-R mice increased anterior tibial displacement compared to the Sham group (P<0.001, 95% CI [-1.509 to-0.966]) and CATT group (P<0.001, 95% CI [-0.841 to-0.298]) at 8 weeks. All mice in the ACL-R group caused cartilage degeneration. The degree of cartilage degeneration in the ACL-R group was higher than in the CATT group (P=0.006) at 8 weeks. The MMP-3-positive cell rate of chondrocytes increased in the ACL-R group than CATT group from 4 weeks (P=0.043; 95% CI [-28.32 to-0.364]) while that of synovial cells increased at 8 weeks (P=0.031; 95% CI [-23.398 to-1.021]). We successfully established a Non-invasive ACL-R model without intra-articular damage. Our model revealed that chondrocytes might react to abnormal mechanical stress prior to synovial cells while the knee OA onset.

Sirt6 attenuates chondrocyte senescence and osteoarthritis progression

Sirt6 has been implicated as a key regulator in aging-related diseases, including osteoarthritis. However, its functional role and molecular mechanism in chondrocyte senescence and osteoarthritis pathophysiology remain largely undefined. Here we show that Sirt6 deficiency exaggerates chondrocyte senescence and osteoarthritis progression, whereas intra-articular injection of adenovirus-Sirt6 markedly attenuates surgical destabilization of medial meniscus-induced osteoarthritis. Mechanistically, Sirt6 can directly interact with STAT5 and deacetylate STAT5, thus inhibiting the IL-15/JAK3-induced STAT5 translocation from cytoplasm to nucleus, which inactivates IL-15/JAK3/STAT5 signaling. Mass spectrometry revealed that Sirt6 deacetylated conserved lysine 163 on STAT5. Mutation of lysine 163 to arginine in STAT5 abolished the regulatory effect of Sirt6. In vivo, specific ablation of Sirt6 in chondrocytes exacerbated osteoarthritis. Pharmacological activation of Sirt6 substantially alleviated chondrocyte senescence. Taken together, Sirt6 attenuates chondrocyte senescence by inhibiting IL-15/JAK3/STAT5 signaling. Targeting Sirt6 represents a promising new approach for osteoarthritis.

Molecular crosstalk between articular cartilage, meniscus, synovium, and subchondral bone in osteoarthritis.

Osteoarthritis (OA) is a common degenerative joint disease worldwide, which is characterized by articular cartilage lesions. With more understanding of the disease, OA is considered to be a disorder of the whole joint. However, molecular communication within and between tissues during the disease process is still unclear. In this study, we used transcriptome data to reveal crosstalk between different tissues in OA. We used four groups of transcription profiles acquired from the Gene Expression Omnibus database, including articular cartilage, meniscus, synovium, and subchondral bone, to screen differentially expressed genes during OA. Potential crosstalk between tissues was depicted by ligand-receptor pairs. During OA, there were 626, 97, 1,060, and 2,330 differentially expressed genes in articular cartilage, meniscus, synovium, and subchondral bone, respectively. Gene Ontology enrichment revealed that these genes were enriched in extracellular matrix and structure organization, ossification, neutrophil degranulation, and activation at different degrees. Through ligand-receptor pairing and proteome of OA synovial fluid, we predicted ligand-receptor interactions and constructed a crosstalk atlas of the whole joint. Several interactions were reproduced by transwell experiment in chondrocytes and synovial cells, including TNC-NT5E, TNC-SDC4, FN1-ITGA5, and FN1-NT5E. After lipopolysaccharide (LPS) or interleukin (IL)-1β stimulation, the ligand expression of chondrocytes and synovial cells was upregulated, and corresponding receptors of co-culture cells were also upregulated. Each tissue displayed a different expression pattern in transcriptome, demonstrating their specific roles in OA. We highlighted tissue molecular crosstalk through ligand-receptor pairs in OA pathophysiology, and generated a crosstalk atlas. Strategies to interfere with these candidate ligands and receptors may help to discover molecular targets for future OA therapy.Cite this article: Bone Joint Res2022;11(12):862-872.

Ageing and Osteoarthritis Synergically Affect Human Synoviocyte Cells: An In Vitro Study on Sex Differences.

Osteoarthritis is a chronic inflammatory disease that affects all of the joints, especially those of the elderly. Aging is a natural and irreversible biological process implicated in the pathophysiology of many chronic diseases, such as osteoarthritis. Inflammation and oxidative stress are the main factors involved in osteoarthritis and aging, respectively, with the production of several pro-inflammatory cytokines such as Interleukin 1β (IL1β) and reactive oxygen species. The aim of the study was to set-up an in vitro model of osteoarthritis and aging, focusing on the sex differences by culturing male and female fibroblast-like synoviocytes (FLSs) with IL1β, hydrogen peroxide (H2O2), IL1β+H2O2 or a growth medium (control). IL1β+H2O2 reduced the cell viability and microwound healing potential, increased Caspase-3 expression and reactive oxygen species and IL6 production; IL1β increased IL6 production more than the other conditions did; H2O2 increased Caspase-3 expression and reactive oxygen species production; Klotho expression showed no differences among the treatments. The FLSs from female donors demonstrated a better response capacity in unfavorable conditions of inflammation and oxidative stress than those from the male donors did. This study developed culture conditions to mimic the aging and osteoarthritis microenvironment to evaluate the behavior of the FLSs which play a fundamental role in joint homeostasis, focusing on the sex-related aspects that are relevant in the osteoarthritis pathophysiology.

Osteoarthritis and microRNAs: Do They Provide Novel Insights into the Pathophysiology of This Degenerative Disorder?

Osteoarthritis (OA) is one of the most prevalent degenerative joint diseases in older adults and a leading cause of disability. Recent research studies have evidenced the importance of mi-croRNAs (miRs) in the pathogenesis of OA. In the present review, we focused on current literature findings on dysregulated miRs involved in the pathophysiology of OA. From the 35 case-control studies including OA patients compared to healthy controls, a total of 54 human miRs were identified to be dysregulated in OA. In total, 41 miRs were involved in the pathophysiological processes of OA, including apoptosis, inflammation, and proliferation, having either a protective or a progressive role in OA. The discovery of altered miR levels in OA patients compared to healthy controls determines a better understanding of the molecular mechanisms involved in the pathophysiology of OA and could open novel horizons in the field of orthopedics.

Semaphorin 3A-Neuropilin-1 Signaling Modulates MMP13 Expression in Human Osteoarthritic Chondrocytes.

Osteoarthritis (OA) is a complex disorder of diarthrodial joints caused by multiple risk factors and is characterized by articular cartilage destruction as well as changes in other articular tissues. Semaphorin 3A (Sema3A), known to be a chemo-repellent for sensory nerve fibers, has recently been implicated in cartilage OA pathophysiology. We demonstrated that the expression of SEMA3A and its receptor neuropilin-1 (NRP1) are synchronously upregulated in chondrocytes isolated from knee cartilage of OA patients compared to non-OA control chondrocytes. In addition, we observed that during in vitro passaging of OA chondrocytes, the Nrp-1 level increases, whereas the Sema3A level decreases. In this study, we aimed to uncover how Sema3A-Nrp-1 signaling affects metabolism and viability of OA chondrocytes via siRNA-mediated inhibition of Nrp-1 expression. We observed a decreased proliferation rate and an increase in adhesion and senescence after Nrp-1 silencing. Moreover, MMP13 gene expression was reduced by approximately 75% in NRP1 knockdown OA chondrocytes, whereas MMP13 expression was induced by Sema3A treatment in control (nt siRNA) OA chondrocytes, accompanied by an impaired AKT phosphorylation. These findings suggest a potential catabolic function of Sema3A signaling in OA chondrocytes by inducing MMP13 expression and by compromising pro-survival AKT activation. We propose that targeting the Sema3A-Nrp-1 signaling axis might be an opportunity to interfere with OA pathogenesis and progression.

Osteoarthritis: insights into pathogenesis and futuristic treatment strategies

&lt;p class="abstract"&gt;Osteoarthritis is the most common musculoskeletal condition world over that causes significant health, economic, and societal burdens. Till date, no therapeutic approaches have been able to stop or delay the progression of osteoarthritis satisfactorily. Structural and clinical features of the disease are characterized by a high inter-patient variability. This heterogeneity is believed to be a major factor associated with the complexity of osteoarthritis and the on-going difficulty to identify a single therapy for all sub-groups. The objective of this review is to highlight recent advances in the understanding of the pathophysiology of osteoarthritis and latest biological treatments available, their limitations and to bring to notice the latest state-of-the-art on-going research on novel therapies. For this study we searched different online databases such as PubMed and Cochrane Library from inception to January 2022. We identified eligible studies on the pathophysiologic findings, prevalence, or incidence of knee osteoarthritis, available treatments, and current research for future therapies. Besides the availability of vast literature on cartilage extracellular matrix and its changes in osteoarthritis, the complicated mechanism of the disease still has missing links in the chain. Presently, biological treatments such as platelet rich plasma, bone marrow mesenchymal stem cells and autologous fragmented adipose tissue containing structural vascular fraction are commonly used. In future, gene therapy could become a potential option for treating the disease.&lt;strong&gt; &lt;/strong&gt;More extensive insights into the pathophysiology of osteoarthritis will be helpful in designing therapies that can curb structural progression and promote cartilage regeneration thus providing more potent relief from painful and disabling condition associated with osteoarthritis.&lt;/p&gt;

Osteoarthritis: New Insight on Its Pathophysiology.

Understanding of the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, as well as the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA physiopathology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms as underlying causes of pain chronicity has been characterized. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. To this aim, this review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insights on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.

Prospects for the use of chondroitin sulfate and glucosamine sulfate in the treatment of patients with obesity-associated osteoarthritis (metabolic syndrome)

The relationship between the pathophysiology of osteoarthritis (OA) and metabolic disorders (metabolic syndrome, obesity) is provided not only by mechanical causes (increased body weight pressure on the joints). A complex of molecular mechanisms, which mediates OA effect on the development of obesity, was established. Excessive activity of toll receptors, the NF-κB cascade, and metabolic disorders of endogenous chondroitin sulfates (CS) lead to chronic inflammation and the development of a complex of comorbid pathologies, including OA, atherosclerosis, and obesity. The relationship between insulin resistance and CS metabolism is also mediated by impaired genomic DNA methylation. Exogenous CS and glucosamine sulfate (GS) used in the long-term treatment of OA also contribute to the inhibition of the pathophysiology of obesity. By inhibiting O-glucosamination of intranuclear proteins (i.e., p53), GS can accelerate lipolysis of visceral fat. Anti-inflammatory effects of CS and GS is associated with inhibition of toll receptors and NF-κB, increased levels of antioxidant enzymes, regulation of expression of fibroblast growth factor 21, activation of adenosine monophosphate-activated protein kinase, and inhibition of secretion of chemoattractant protein MCP-1 and pancreatic lipase. Positive effect of CS and its oligosaccharides exposure on the pathophysiology of metabolic disorders is associated not only with a decrease in inflammation and normalization of fat metabolism but also with an improvement in the state of the intestinal microbiota. Experimental and clinical studies confirm the effects of CS and GS on body mass control. CS and GS are effective and safe when used in patients with OA associated with metabolic syndrome and/or obesity.

Phenotypic and functional characterisation of synovial fluid-derived neutrophils in knee osteoarthritis and knee infection

An increase in the number of neutrophils (NEUs) has long been associated with infections in the knee joints; however, their impact on knee osteoarthritis (KOA) pathophysiology remains largely unexplored. This study compared the phenotypic and functional characteristics of synovial fluid (SF)-derived NEUs in KOA and knee infection (INF). KOA NEUs were characterised by a lower expression of CD11b, CD54, and CD64 and higher expression of CD62L, TLR2, and TLR4 compared with INF NEUs. Except for CCL2, lower levels of inflammatory mediators and proteases were detected in KOA SF than in INF SF. Functionally, KOA NEUs displayed increased reactive oxygen species production and phagocytic activity compared with INF NEUs. Moreover, KOA and INF NEUs differed in cell sizes, histological characteristics of the surrounding synovial tissues, and their effects on the endothelial cells assessed by human umbilical vein endothelial cells. When KOA patients were subdivided based on the SF NEU abundance, patients with high NEUs (10%-60%) were characterised by i) elevated SF protein levels of TNF-α, IL-1RA, MMP-9, sTREM-1, VILIP-1 and ii) lower CD54, CD64, TLR2 and TLR4 expression compared to patients with low NEUs (<10%). Analysis of paired SF samples suggests that low or high NEU percentages, respectively, persist throughout the course of disease. Our findings suggest that NEU may play a significant role in KOA pathophysiology. Further studies should explore the mechanisms that contribute to the increased number of NEUs in SF and the clinical consequences of neutrophilic phenotype in KOA.

Circ_0022383 alleviates IL-1β-induced apoptosis, inflammation and extracellular matrix degeneration in osteoarthritis cell model by miR-3619-5p/SIRT1 axis

BackgroundCircular RNAs (circRNAs) have been identified to play roles in cartilage homeostasis and chondrocyte development, and be associated with osteoarthritis (OA) pathophysiology. Here, we aimed to investigate the role and mechanism of circ_0022383 on OA progression. MethodsChondrocytes in functional groups were treated with interleukin (IL)-1β. The levels of genes and proteins were assayed by qRT-PCR and western blotting. Cell proliferation and apoptosis were evaluated by cell counting kit-8 assay, 5-Ethynyl-2′-deoxyuridine (Edu) assay, and flow cytometry, respectively. The inflammation and extracellular matrix (ECM) degeneration were determined by assessing the activity of IL-6, tumor necrosis factor (TNF-α), Aggrecan (ACAN), collagen type II α 1 chain (COL2A1) and ADAMTS5 proteins. The binding between miR-3619-5p and circ_0022383 or silent information regulator 1 (SIRT1) was confirmed by dual-luciferase reporter, RIP and RNA pull-down assays. ResultsCirc_0022383 expression was lower in the cartilages of OA patients and IL-1β-induced primary chondrocytes. Functionally, ectopic overexpression of circ_0022383 alleviated IL-1β-induced proliferation arrest, apoptosis, the release of IL-6 and TNF-α, as well as the decrease of ACAN and COL2A1 and the increase of ADAMTS5 level in chondrocytes. Mechanistically, circ_0022383 acted as a sponge for miR-3619-5p, which was verified to target SIRT1. Rescue experiments showed that miR-3619-5p up-regulation reversed the protective effects of circ_0022383 on IL-1β-stimulated chondrocytes. Additionally, miR-3619-5p inhibition abolished IL-1β-induced apoptosis, inflammation and ECM degeneration in chondrocytes, which were counteracted by SIRT1 silencing. ConclusionCirc_0022383 protected chondrocytes from IL-1β-induced apoptosis, inflammation and ECM degeneration by miR-3619-5p/SIRT1 axis, inspiring future therapy development for OA prevention.

Exploration of novel drug delivery systems in topical management of osteoarthritis.

Osteoarthritis is one of the foremost disabling disorders in the world. There is no definitive treatment to prevent the progression of osteoarthritis. Hence, palliative treatment aims at minimizing pain, disability and improving function, performance and quality of life. Oral administration of nonsteroidal anti-inflammatory drug is associated with number of adverse effects and reduced therapeutic efficacy. Intra-articular injection has been the preferred route of drug administration. However, the clearance of drug from the arthritic site, risk of infections, cost and the pain associated with frequent injections make this route highly non-compliant to patients. Since osteoarthritis is a chronic condition which requires treatment for prolonged duration, there is an urgent need for another administration route which circumvents the hindrances linked with intra-articular route. Transdermal route across the skin locally at the osteoarthritis site could help in surpassing the disadvantages associated with intra-articular route. However, traversing skin barrier and reaching the chondrocytes with sufficient amount of the drug is extremely difficult. Nanocarrier-based approaches could hold an answer to the said shortcomings owing to their reduced size, targeting tunability and site specificity. In this article, we discuss the pathophysiology of osteoarthritis, molecular targets, and utilization of nanocarrier-based approaches to strategize the treatment of osteoarthritis in a new direction, i.e. topical delivery of nanocarriers in osteoarthritis.

RNA binding proteins in osteoarthritis.

Osteoarthritis (OA) is a common chronic degenerative joint disease worldwide. The pathological features of OA are the erosion of articular cartilage, subchondral bone sclerosis, synovitis, and metabolic disorder. Its progression is characterized by aberrant expression of genes involved in inflammation, proliferation, and metabolism of chondrocytes. Effective therapeutic strategies are limited, as mechanisms underlying OA pathophysiology remain unclear. Significant research efforts are ongoing to elucidate the complex molecular mechanisms underlying OA focused on gene transcription. However, posttranscriptional alterations also play significant function in inflammation and metabolic changes related diseases. RNA binding proteins (RBPs) have been recognized as important regulators in posttranscriptional regulation. RBPs regulate RNA subcellular localization, stability, and translational efficiency by binding to their target mRNAs, thereby controlling their protein expression. However, their role in OA is less clear. Identifying RBPs in OA is of great importance to better understand OA pathophysiology and to figure out potential targets for OA treatment. Hence, in this manuscript, we summarize the recent knowledge on the role of dysregulated RBPs in OA and hope it will provide new insight for OA study and targeted treatment.

Level dependent alterations in human facet cartilage mechanics and bone morphometry with spine degeneration.

The zygapophyseal joints of the spine, also known as the facet joints, are paired diarthrodial joints posterior to the intervertebral disc and neural elements. The pathophysiology of facet osteoarthritis (OA), as well as crosstalk between the disc and facets, remains largely understudied compared to disc degeneration. The purpose of this study was to characterize alterations to human facet cartilage and subchondral bone across a spectrum of degeneration and to investigate correlations between disc and facet degeneration. Human lumbar facet articular surfaces from six independent donors were subject to creep indentation mechanical testing to quantify cartilage mechanical properties, followed by microcomputed tomography (µCT) analyses for subchondral bone morphometry. The degenerative state of each articular surface was assessed via macroscopic scoring and via Osteoarthritis Research Society International histopathology scoring. Our data suggest reduced facet cartilage compressive and tensile moduli and increased permeability with increasing degenerative grade, particularly at the lower levels of the spine. µCT analyses revealed spinal level-dependent alterations to the subchondral bone, with an increase in trabecular bone at the L4-L5 level, but a decrease at the upper levels of the lumbar spine with increasing degenerative grade. Cortical bone volume fraction was generally decreased with increasing degenerative grade across spinal levels. Correlation analysis revealed several associations between quantitative measures of disc degeneration and facet OA. This study showed that alterations in the mechanical properties of facet cartilage and in the structural properties of facet subchondral bone correlated with aspects of disc degeneration and were highly dependent on spinal level.

The Involvement of Neutrophils in the Pathophysiology and Treatment of Osteoarthritis.

Osteoarthritis (OA) is a chronic disability that significantly impairs quality of life. OA is one of the most prevalent joint pathologies in the world, characterized by joint pain and stiffness due to the degeneration of articular cartilage and the remodeling of subchondral bone. OA pathogenesis is unique in that it involves simultaneous reparative and degradative mechanisms. Low-grade inflammation as opposed to high-grade allows for this coexistence. Previously, macrophages and T cells have been identified as playing major roles in the inflammation and destruction of OA joints, but recent studies have demonstrated that neutrophils also contribute to the pathogenesis. Neutrophils are the first immune cells to enter the synovium after joint injury, and neutrophilic activity is indispensably a requisite for the progression of OA. Neutrophils act through multiple mechanisms including tissue degeneration via neutrophil elastase (NE), osteophyte development, and the release of inflammatory cytokines and chemokines. As the actions of neutrophils in OA are discovered, the potential for novel therapeutic targets as well as diagnostic methods are revealed. The use of chondrogenic progenitor cells (CPCs), microRNAs, and exosomes are among the newest therapeutic advances in OA treatment, and this review reveals how they can be used to mitigate destructive neutrophil activity.

Nutrition risk, physical activity and fibre intake are associated with body composition in OA: analysis of the Canadian Longitudinal Study on Aging

ObjectiveSarcopenic obesity is a key feature in osteoarthritis (OA). While ideal OA treatment involves physical activity and diet, how diet influences OA pathophysiology is unclear. We explored the associations between...

Innate Immunity at the Core of Sex Differences in Osteoarthritic Pain?

Osteoarthritis (OA) is a progressive whole-joint disease; no disease-modifying drugs are currently available to stop or slow its process. Symptoms alleviation is the only treatment option. OA is the major cause of chronic pain in adults, with pain being the main symptom driving patients to seek medical help. OA pathophysiology is closely associated with the innate immune system, which is also closely linked to pain mediators leading to joint pain. Pain research has shown sex differences in the biology of pain, including sexually dimorphic responses from key cell types in the innate immune system. Not only is OA more prevalent in women than in men, but women patients also show worse OA outcomes, partially due to experiencing more pain symptoms despite having similar levels of structural damage. The cause of sex differences in OA and OA pain is poorly understood. This review provides an overview of the involvement of innate immunity in OA pain in joints and in the dorsal root ganglion. We summarize the emerging evidence of sex differences regarding innate immunity in OA pain. Our main goal with this review was to provide a scientific foundation for future research leading to alternative pain relief therapies targeting innate immunity that consider sex differences. This will ultimately lead to a more effective treatment of pain in both women and men.

Concept End Points Informing Design Considerations for Confirmatory Clinical Trials in Osteoarthritis.

There is an unmet need for therapies that target the underlying pathophysiology of osteoarthritis (OA). However, defining appropriate measures for clinical trials of such therapies is challenging. Our objective was to propose concept clinical end points that directly capture clinical benefit in this setting and evaluate the feasibility of their use. This analysis used the multicenter, longitudinal, observational Osteoarthritis Initiative (OAI) database. OAI participants primarily had knee OA, with follow-up of up to 9 years and assessments of joints, surgical interventions, performance outcomes, and patient-reported outcomes. We examined this data set to identify existing outcome measures of direct clinical benefit. We evaluated the feasibility of conducting trials using these candidate end points by estimating incidence rates and resulting required sample sizes and study durations in time-to-event analyses. We identified candidate end points based on total knee replacement (TKR) and composite end points defined by TKR and conservative thresholds of patient-reported outcomes of pain and function. Using time to TKR as an end point, a study with an average follow-up time of 3 years requires approximately 3,000 to 18,000 subjects, depending on effect size. Alternatively, for a composite end point, such as "time to TKR or severe pain or severely impaired functioning," the required sample sizes ranged from approximately 2,000 to 11,000 for a 3-year study. The proposed concept end points can reliably and feasibly evaluate the effectiveness of therapies for this unmet need. In particular, the composite end point approach can substantially reduce sample sizes (up to approximately 40%) compared to the use of TKR alone.