Etiology Of Osteoarthritis Research Articles

SEMI-QUANTITATIVE AND QUANTITATIVE CARTILAGE IMPROVEMENT AFTER INTRA-ARTICULAR INJECTION OF ICM-203 IN CANINE OA MODEL

Purpose: While inflammation in osteoarthritis (OA) needs to be controlled to attenuate OA pathogenesis, maintenance of proper dynamics of chondrocyte physiology would also be critical to inhibit the onset and early progression of OA. Due to the complicated etiology of OA, there are no effective disease-modifying treatments to date, and significant unmet medical needs exist for a disease-modifying OA drug (DMOAD). Nkx3.2 was initially identified as a pro-chondrogenic factor promoting cartilage development.

Causal Associations of Circulating Lipids with Osteoarthritis: A Bidirectional Mendelian Randomization Study.

Osteoarthritis (OA) imposes an increasing social burden due to global activity limitations, especially among the aged. Links between circulating lipids and OA have been reported; however, confounding data from observational studies have hindered causal conclusions. We used Mendelian randomization (MR) approach to evaluate the genetic causal effects of circulating apolipoproteins and lipoprotein lipids on OA risk. Genetic instruments at the genome-wide significance level (p < 5 × 10−8) were selected from genome-wide association studies (n = 393,193–441,016 individuals). Summary-level OA data were obtained from the UK Biobank (39,427 cases, 378,169 controls). Bidirectional two-sample Mendelian randomization (MR) analyses used MR-Egger, weighted median, and MR-PRESSO for sensitivity analysis. Genetic predisposition to 1-SD increments of Apolipoprotein B (APOB), and low-density lipoprotein (LDL) was associated with a decreased risk of knee or hip OA (KHOA) (odds ratio (OR) = 0.925, 95% confidence interval (95% CI): 0.881–0.972, p = 0.002; OR = 0.898, 95% CI: 0.843–0.957, p = 0.001) and hip OA (HOA) (OR = 0.894; 95% CI: 0.832–0.961, p = 0.002; OR = 0.870 95% CI: 0.797–0.949, p = 0.002). Genetically predicted APOB showed an association with knee OA (KOA) (OR per SD increase, 0.930, 95% CI: 0.876–0.987, p = 0.016). The OR of KOA was 0.899 (95% CI: 0.835–0.968, p = 0.005) for a 1-SD increase in LDL. Apolipoprotein A1, high-density lipoprotein, and triglycerides showed no association. Inverse MR showed no causal effect of KOA, HOA, or KHOA on these serum lipids. Distinct protective genetic-influence patterns were observed for APOB and LDL on OA, offering new insights into relationships between lipids and OA risk and a better understanding of OA etiology.

Sprifermin for Treatment of Osteoarthritis: Recombinant Fibroblast Growth Factor 18 as a Possible Disease-Modifying Knee Osteoarthritis Drug

Osteoarthritis (OA) is a major cause of pain and disability in adults, affecting approximately 150 million people worldwide. It is most prevalent in knees and hips. Major risk factors are age, female sex, prior joint injury, and obesity. OA causes significant personal and steeply rising socio-economical costs in ageing populations. OA is characterized by progressive cartilage damage and inflammation. In later stages, it affects the subchondral bone, bone marrow, ligaments, tendons, and nerves und eventually leads to joint failure. Symptoms include pain, joint swelling, and stiffness. Therapies are symptomatic and focus on pain relief and measures to improve mobility, or, ultimately, joint replacement. So far, no drugs that could prevent or slow down disease progression are available. Based on promising in vitro and preclinical studies, recombinant fibroblast growth factor (FGF) 18 (sprifermin; Merck Serono) has come into focus as a potential disease-modifying OA drug (DMOAD). Three randomized controlled trials (RCTs) investigating the safety and efficacy of intraarticularly (i.a.) injected sprifermin application in patients with knee OA have been completed so far. Data from these trials, post hocanalyses and follow-ups provide have evidenced that i.a. sprifermin induced a significant and sustained increase in cartilage thickness and volume without specific adverse effects, but in terms of clinical symptoms or physical joint function sprifermin did not cause significant improvements compared to placebo treatment in whole study populations. However, significant pain reduction was observed in a “subgroup at risk” of patients with more severe disease states, indicating that under certain disease conditions the structural benefit improvements could translate into clinical benefit. This calls for larger RCTs allowing e.g., for disease state or risk factor-specific stratification of patients and longer follow-ups to substantiate the efficacy of sprifermin as a possible DMOAD. This review gives an overview on the prevalence, etiology and socio-economic burden of OA, its pathogenesis as well as the current treatment options of the disease. It summarizes the role of FGF-18 in chondrocyte and cartilage (patho)physiology and addresses the question of evidence for the efficacy and safety of i.a. sprifermin injection in patients with knee OA based on trial outcomes and literature data.

Patient beliefs about who and what influences their hip and knee osteoarthritis symptoms and progression.

Osteoarthritis management aims to reduce pain and improve function. Many factors affect whether patients follow recommended strategies. Locus of control refers to individual beliefs around who and what influences health. Locus of control is related to the treatment strategies patients prefer. Currently, no studies explore locus of control in non-surgical management of osteoarthritis. To explore patients' beliefs about the influences on their osteoarthritis symptoms and disease progression. Semi-structured interviews were conducted with individuals experiencing self-reported hip and/or knee osteoarthritis who had at least one joint that had not undergone replacement surgery. We used a qualitative description approach and the Braun and Clarke method for thematic analysis. Participants' locus of control classifications-internal, chance, doctors, or other people-were based on the Multidimensional Health Locus of Control (MHLC) Scales Form C score. Locus of control was discussed in relation to aetiology, progression, and symptoms. Participants' opinions varied on whether their osteoarthritis progression could be influenced. 46% of participants attributed control to other people. Most participants believed that a previous injury had caused their osteoarthritis and that both themselves and others had some influence over their osteoarthritis symptoms, regardless of their locus of control classification. This research highlights the need for education about: the aetiology of osteoarthritis, the link between management and progression, and patient management of osteoarthritis. Further research is required to discern why expected patterns were not observed between participants' beliefs and locus of control classifications.

Role of the Osteochondral Unit in the Pathogenesis of Osteoarthritis: Focus on the Potential Use of Clodronate

Osteoarthritis (OA) is a chronic disease characterized by inflammation and progressive deterioration of the joint. The etiology of OA includes genetic, phlogistic, dismetabolic and mechanical factors. Historically, cartilage was considered the target of the disease and therapy was aimed at protecting and lubricating the articular cartilage. The osteochondral unit is composed of articular cartilage, calcified cartilage, and subchondral and trabecular bone, which work synergistically to support the functional loading of the joint. Numerous studies today show that OA involves the osteochondral unit, with the participation therefore of the bone in the starting and progression of the disease, which is associated with chondropathy. Cytokines involved in the process leading to cartilage damage are also mediators of subchondral bone edema. Therefore, OA therapy must be based on the use of painkillers and bisphosphonates for both the control of osteometabolic damage and its analgesic activity. Monitoring of the disease of the osteochondral unit must be extensive, since bone marrow edema can be considered as a marker of the evolution of OA. In the present review, we discuss some of the pathogenetic mechanisms associated with osteoarthritis, with a particular focus on the osteochondral unit and the use of clodronate.

Tetra-primers ARMS-PCR Based Association Analyses of Synonymous and Intronic Variants in the ADAM12 Gene with Susceptibility to Knee Osteoarthritis: A Case-Control Study.

Genetic variations in a disintegrin and metalloprotease 12 (ADAM12) gene may contribute to develop Osteoarthritis (OA) that is characterized by cartilage matrix degradation and osteophytes formation. Therefore, the aim of present study was to analyze the association between the ADAM12 gene variants and knee OA predisposition. Tetra-primers ARMS-PCR was employed, to genotype the ADAM12 gene polymorphisms (rs1044122 and rs1871054) in 400 knee OA patients and equal number of age-matched controls. The association between ADAM12 gene variants and OA susceptibility was estimated using the Chi-square, logistic regression, haplotypes and linkage analyses. A significant association of rs1044122 (genotype: χ2 = 18.94; P < 0.001, allele: χ2 = 19.10; P < 0.001) and rs1871054 (genotype: χ2 = 10.04; P = 0.007, allele: χ2 = 10.57; P = 0.001) was observed with increased OA susceptibility. The variant genotype of rs1044122 increased OA risk more than twice [odds ratio (OR) 2.20; P = 0.001] and the risk was higher in females (OR 2.43; P = 0.001). The variant genotype of rs1871054 was perceived to almost double the risk in females (OR 1.97; P = 0.003). Moreover, a significant association of rs1044122 and rs1871054 under the additive genetic model (P < 0.001 and P = 0.002, respectively) was observed. The targeted ADAM12 gene polymorphisms, showed significant association with knee OA susceptibility. Females harboring the polymorphisms might be at risk. Besides, the haplotype CC of rs1044122 and rs1871054 in the ADAM12 gene may double knee OA risk. These findings may help in determining the etiology of OA and recognizing the people at risk of developing knee OA.

Cartilage tissue engineering: From proinflammatory and anti‑inflammatory cytokines to osteoarthritis treatments (Review).

Osteoarthritis (OA), one of the most common joint diseases, is characterized by fibrosis, rhagadia, ulcers and attrition of articular cartilage due to a number of factors. The etiology of OA remains unclear, but its occurrence has been associated with age, obesity, inflammation, trauma and genetic factors. Inflammatory cytokines are crucial for the occurrence and progression of OA. The intra-articular proinflammatory and anti-inflammatory cytokines jointly maintain a dynamic balance, in accordance with the physiological metabolism of articular cartilage. However, dynamic imbalance between proinflammatory and anti-inflammatory cytokines can cause abnormal metabolism in knee articular cartilage, which leads to deformation, loss and abnormal regeneration, and ultimately destroys the normal structure of the knee joint. The ability of articular cartilage to self-repair once damaged is limited, due to its inability to obtain nutrients from blood vessels, nerves and lymphatic vessels, as well as limitations in the extracellular matrix. There are several disadvantages inherent to conventional repair methods, while cartilage tissue engineering (CTE), which combines proinflammatory and anti-inflammatory cytokines, offers a new therapeutic approach for OA. The aim of the present review was to examine the proinflammatory factors implicated in OA, including IL-1β, TNF-α, IL-6, IL-15, IL-17 and IL-18, as well as the key anti-inflammatory factors reducing OA-related articular damage, including IL-4, insulin-like growth factor and TGF-β. The predominance of proinflammatory over anti-inflammatory cytokine effects ultimately leads to the development of OA. CTE, which employs mesenchymal stem cells and scaffolding technology, may prevent OA by maintaining the homeostasis of pro- and anti-inflammatory factors.

Conservative treatment options for symptomatic thumb trapeziometacarpal joint osteoarthritis

There are numerous non-surgical treatment options for basal thumb osteoarthritis (OA). Aetiology, clinical appearance and diagnosis of basal thumb OA, explanation of the individual non-surgical treatment options, presentation of the current state of studies. Search for case analyses, studies, systematic reviews and meta-analyses using PubMed and LIVIVO. Intraarticular injections have no more than short-term success with therisk of infection, which should not be underestimated. Radiotherapy seems to be an effective treatment, but little research has been done on this. Physiotherapy and splinting treatment promise long-term improvement of clinical symptoms and hand function. Basal thumb OA is acommon and serious condition, which in the case of continuous pain should be diagnosed and treated adequately. Amulti-modal therapeutic regimen with avoidance of repetitive intra-articular injections seems to provide the best long-term results.

Cam morphology is associated with MRI-defined cartilage defects and labral tears: a case–control study of 237 young adult football players with and without hip and groin pain

ObjectiveFootball players are at risk of developing hip osteoarthritis (OA). Cam morphology (present in almost two of every three football players) may explain this heightened risk, but there is limited...

Recent Advances in Pharmacological Intervention of Osteoarthritis: A Biological Aspect.

Osteoarthritis (OA) is a degenerative joint disease in the musculoskeletal system with a relatively high incidence and disability rate in the elderly. It is characterized by the degradation of articular cartilage, inflammation of the synovial membrane, and abnormal structure in the periarticular and subchondral bones. Although progress has been made in uncovering the molecular mechanism, the etiology of OA is still complicated and unclear. Nevertheless, there is no treatment method that can effectively prevent or reverse the deterioration of cartilage and bone structure. In recent years, in the field of pharmacology, research focus has shifted to disease prevention and early treatment rather than disease modification in OA. Biologic agents become more and more attractive as their direct or indirect intervention effects on the initiation or development of OA. In this review, we will discuss a wide spectrum of biologic agents ranging from DNA, noncoding RNA, exosome, platelet-rich plasma (PRP), to protein. We searched for key words such as OA, DNA, gene, RNA, exosome, PRP, protein, and so on. From the pharmacological aspect, stem cell therapy is a very special technique, which is not included in this review. The literatures ranging from January 2016 to August 2021 were included and summarized. In this review, we aim to help readers have a complete and precise understanding of the current pharmacological research progress in the intervention of OA from the biological aspect and provide an indication for the future translational studies.

Nanoparticle-Based Drug Delivery System—A Target Strategy for Osteoarthritis Treatment

Osteoarthritis (OA) is a bone and joint disease with pathological characteristics such as articular cartilage degeneration injury and synovial and subchondral bone reactive hyperplasia. Once cartilage is damaged, it is difficult to repair it by itself. Current clinical practice is mainly limited to symptomatic treatment, not changing the degenerative process of osteoarthritis. The important goal of nanomedicine is targeted delivery. Nanoparticles (NPs) can provide many unique potential functions for the targeted treatment of arthritis. This review summarizes the research progress of nanomaterials as a drug delivery system in the treatment of osteoarthritis from three aspects: (1) the etiology of OA and the current research status of applying nanoparticles to treat OA, (2) the construction of osteoarthritis models, and (3) the classification of nanoparticle-based drug delivery systems.

Conservative Treatment of Ankle Osteoarthritis.

Despite the disabling nature of ankle osteoarthritis (OA), there is poor scientific evidence for a conservative treatment compared to the hip and knee OA. In this regard, most of the treatment options in use are not based on clinical studies of the ankle, and they are extracted from evidence obtained from clinical studies of other lower limb joints. However, this does not seem to be a good idea, since the aetiology of ankle OA is quite different from that of the hip or knee. Nonpharmacological and pharmacological treatments such as nonsteroidal anti-inflammatory drugs, hyaluronic acid, corticosteroid, platelet-rich plasma injection and mesenchymal stem cells injections have been reported. However, further research is required in this field to obtain a specific clinical practice guideline for the conservative treatment of ankle OA.

The effects of orthopedic pathological conditions and systemic diseases on the prevalence of hip osteoarthritis in Modern African- and European-Americans.

Osteoarthritis (OA) is a leading cause of disability among aging adults. In the U.S., many individuals living with total hip replacements attribute OA as the cause. However, the majority of anthropological OA research excludes pathological individuals (i.e., individuals with systemic disease, traumatic injuries, or orthopedic devices). Thus, little is known about how implants and pathological conditions impact OA beyond a general acceptance that they likely increase OA risk. This study adds to the skeletal research surrounding OA by directly investigating its relationship with age, disease, and implants. The proximal femora of 186 African- and European-American individuals (21-95 years old) from the Edmonds Orthopedic Pathology Collection (National Museum of Health and Medicine; Armed Forces Institute of Pathology) were analyzed. The individuals were grouped into three cohorts: disease; non-disease; and previous injury/implant. Jurmain's (1990) ordinal scoring method was used to categorize OA changes as: none/slight; moderate; severe; and ankylosis. Intra-rater reliability for the scoring of OA was perfect, while inter-rater reliability was moderate. Results from Chi-square tests, exploratory data analysis, and ordinal logistic regression showed that there was a statistically significant relationship (p < 0.001) between degree of OA, age, recorded disease (e.g., cancer), and evidence of previous injury (i.e., healed fractures, fracture fixation devices). In contrast with the expectation that different populations exhibit different patterns of OA, no significant sex or ancestry effects were observed. These results help researchers better understand the etiology and contemporary risk factors of OA as well as identifying an additional subset of the population who may be at greater risk for developing OA - i.e., individuals with fractures, implants, and systemic disease, especially those in older age cohorts (60+ years).

Stem Cells in Autologous Microfragmented Adipose Tissue: Current Perspectives in Osteoarthritis Disease.

Osteoarthritis (OA) is a chronic debilitating disorder causing pain and gradual degeneration of weight-bearing joints with detrimental effects on cartilage volume as well as cartilage damage, generating inflammation in the joint structure. The etiology of OA is multifactorial. Currently, therapies are mainly addressing the physical and occupational aspects of osteoarthritis using pharmacologic pain treatment and/or surgery to manage the symptomatology of the disease with no specific regard to disease progression or prevention. Herein, we highlight alternative therapeutics for OA specifically considering innovative and encouraging translational methods with the use of adipose mesenchymal stem cells.

Articular cartilage regeneration by activated skeletal stem cells

Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2–4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5–7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA. Endogenous skeletal stem cells are recruited to form cartilage in mice when stimulated by microfracture surgery together with localized delivery of growth factors, pointing to a new approach for treating cartilage defects.

Phytochemical Analysis and Anti-Inflammatory and Anti-Osteoarthritic Bioactive Potential of Verbascum thapsus L. (Scrophulariaceae) Leaf Extract Evaluated in Two In Vitro Models of Inflammation and Osteoarthritis.

Osteoarthritis (OA) is a complex disease, source of pain and disability that affects millions of people worldwide. OA etiology is complex, multifactorial and joint-specific, with genetic, biological and biomechanical components. Recently, several studies have suggested a potential adjuvant role for natural extracts on OA progression, in terms of moderating chondrocyte inflammation and following cartilage injury, thus resulting in an overall improvement of joint pain. In this study, we first analyzed the phenylethanoid glycosides profile and the total amount of polyphenols present in a leaf aqueous extract of Verbascum thapsus L. We then investigated the anti-inflammatory and anti-osteoarthritic bioactive potential of the extract in murine monocyte/macrophage-like cells (RAW 264.7) and in human chondrocyte cells (HC), by gene expression analysis of specifics inflammatory cytokines, pro-inflammatory enzymes and metalloproteases. Six phenylethanoid glycosides were identified and the total phenolic content was 124.0 ± 0.7 mg gallic acid equivalent (GAE)/g of extract. The biological investigation showed that the extract is able to significantly decrease most of the cellular inflammatory markers, compared to both control cells and cells treated with Harpagophytum procumbens (Burch.) DC. ex Meisn, used as a positive control. Verbascum thapsus leaf aqueous extract has the potential to moderate the inflammatory response, representing an innovative possible approach for the inflammatory joint disease treatment.

The Role of Proteinases in Osteoarthritis: A Brief Review of New Potent Cartilage Metabolism Therapeutic Target

Osteoarthritis (OA) is the most frequent form of degenerative joint disease that becomes a major source of disability worldwide. The loss of articular cartilage is the central etiology of osteoarthritis. Cartilage is solely composed of one cell type, the chondrocytes, which are surrounded by a large volume of extracellular matrix (ECM). Extracellular matrix components consist of two main macromolecules, namely collagen and aggrecan. The degradation of these molecules plays a significant role in OA pathological process, although degradation of less abundant molecules composing the matrix organization is also likely to contribute to disease progression. Several proteinases, including matrix metalloproteinase 13 (MMP-13) and A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS) -4 and -5, are known to involve in the matrix degradation of cartilage structure. A comprehensive understanding of the various factors and pathways involved in the regulation of MMP-13, ADAMTS-4, and ADAMTS-5 is essential in regard to osteoarthritis management, as they have great potential in future therapies.

The association between knee osteoarthritis and polycystic ovary syndrome in postmenopausal women: preliminary results.

The comorbidity of many risk factors associated with the etiology of osteoarthritis (OA) and polycystic ovary syndrome (PCOS) is commonly observed. However, to the best of our knowledge, there are no studies in literature on the relationship between PCOS history and knee OA development in postmenopausal women. A total of 120 postmenopausal women diagnosed with knee osteoarthritis who underwent surgical treatment in our orthopedic clinic and, 80 postmenopausal women who referred to our orthopedic clinic but did not have knee osteoarthritis were randomly included in our study. Body Mass Index (BMI) values, PCOS history and demographic data of the patients in both groups were examined. PCOS was found to be an independent risk factor for OA. PCOS was 2.734 times effective in the development of knee OA, Odd ratio (95% confidence interval) = 2.734 (1.206-6.198) and p-value 0.016. BMI was found to be an independent risk factor for OA. BMI between 25-30 was found to be 2.783 times more effective on knee OA development when compared with BMI<25, Odd Ratio (95% confidence interval) = 2.783 (1.324-5.852) and p-value 0.07. In addition, BMI>30 was found to be 9.237 times more effective on knee OA development when compared with BMI<25, Odd Ratio (95% confidence interval) = 9.237 (3.992-21.374) and p-value <0.001. The history of PCOS was found to be statistically significantly higher in the knee OA group. BMI and PCOS were found to be independent risk factors in the development of knee OA.

The association between statistical shape variations of the hip and the presence of a cartilage defect or labral tear on MRI in high-impact athletes

Purpose: Hip osteoarthritis (OA) is highly prevalent in older people and a leading cause of physical disability worldwide. Although the etiology of hip OA is multifactorial, recent evidence has demonstrated that bony hip morphologies, such as cam morphology and acetabular dysplasia, are associated with an increased risk of developing hip OA in the elderly. Other morphological variants might also pose a risk; statistical shape modeling (SSM) can be used to identify these variants by quantifying the whole radiographic hip shape.

PLasma proteomics identifies crtac1 as a biomarker for osteoarthritis severity and progression

Purpose: Accurate biomarkers for diagnosis and prediction of osteoarthritis (OA) are needed. In addition, biomarkers have the potential to serve as a measure of the different pathological processes underlying OA. Here, we report on a proteomics screen targeted at two important pathways thought to underlie the etiology of OA: the inflammation and metabolic pathways. The aim of this study was to identify a robust biomarker for OA severity and progression. Methods: We used data from the Rotterdam Study (RS), a population based prospective study with participants aged 45 and older. Participants of the RS underwent blood and radiographic measurements at baseline and after a mean follow-up time of 5 years. We measured 184 proteins (inflammation and cardiometabolic panel) in plasma from 3,517 participants in the RS using the Olink platform. We estimated the association for all available proteomic biomarkers with OA in knee, hip and hand. Specifically, phenotype-protein associations were estimated in three ways: 1) Cross-sectionally of overall OA burden, where we computed a weighted overall OA-score by adding up standardized score for knees, hands and hips for each individual; 2) Cross-sectionally in all joints separately, where we analyzed severity of OA by adding up bilateral KL-scores for knee or hip and all joints of the left and right hand (total amount of joints=30); 3) Longitudinally in knee and hip separately, where we defined cases of OA progression as individuals with at least 1 unit increase in KL-grade, excluding progressors from KL0 to KL1. For each of the three scenarios, we analyzed the relationships with multivariate regression models using linear models for continuous outcomes and generalized linear models with binomial link function for dichotomous outcomes. In model 1, we adjusted for age, sex and cell counts, whereas in model 2 we additionally adjusted for BMI. We report effect estimate (β) per standard deviation (SD) change in protein levels with 95% Confidence Interval (CI) and nominal p-value (significance level<0.05) for each protein. We used FDR-correction for multiple testing. All statistical analyses were performed in R version 3.5.2. Results: We found in total 56 proteins that were significantly associated with one or more OA-outcomes at nominal level. In total, we found 12 significant proteins to be associated with overall OA burden (Figure 1. illustrates these associations in decreasing order of the significance level), out of which 7 proteins stayed significant after BMI adjustment. The most robust association was found between the level of circulating Cartilage acidic protein 1 (CRTAC1) and overall OA burden (β=0.18, p=3.16 x10-6; FDR-corrected p=2.74 x10-4). When we examined the joints separately, we observed associations with severity of OA in the knee (β=0.16, p=1.0 x10-5) and hand (β=0.086, p=9.0 x10-4), while a similar trend was seen in hip (β=0.08, p=0.12), although power in hip was limited in our study. The association with baseline CRTAC1 was also found for progression in knee (β=0.21, p=0.016) and hip (β=0.18, p=0.062). These associations were independent of BMI. Among the findings were several other promising biomarkers, e.g. MMP-10, which we observed to be associated with overall OA burden (β=-0.104, p=0.01; FDR-corrected p=0.28), as well as for severity of hand OA (β=-0.09, p=6.7x10-4) and progression of knee OA (β=-0.24, p=7.3 x10-3). Additionally, COMP, a well-known biomarker for OA, was also found significant for overall OA burden (β=0.15, p=1.17 x10-4; FDR-corrected p=5 x10-3), OA severity in hand (β=0.10, p=5 x10-5) and knee (β=0.09, p=0.01). In a multivariable adjusted model with both COMP and CRTAC1 included, the estimate and significance of the latter remained while the estimate of COMP lowered and lost its significance. Conclusions: We identified a number of promising biomarkers reflecting overall OA burden and increased risk for OA progression. The CRTAC1 protein is a robust, promising biomarker for osteoarthritis severity and progression. Moreover, we showed that the association of CRTAC1 is independent from COMP. This protein is a glycosylated extracellular matrix protein that is found in the interterritorial matrix of articular deep zone cartilage. This protein can also be used to distinguish chondrocytes from osteoblasts and mesenchymal stem cells in culture. This suggests that CRTAC1-levels reflects a cartilage-specific process in the joint. Such a biomarker might be useful for targeting the right patients for clinical trials and designing novel therapies for OA.