Identification and characterization of two consistent osteoarthritis subtypes by transcriptome and clinical data integration.

OBJECTIVE: To identify OA subtypes based on cartilage transcriptomic data in cartilage tissue and characterize their underlying pathophysiological processes and/or clinically relevant characteristics. METHODS: This study includes n = 66 primary OA patients (41 knees and 25 hips), who underwent a joint replacement surgery, from which macroscopically unaffected (preserved, n = 56) and lesioned (n = 45) OA articular cartilage were collected [Research Arthritis and Articular Cartilage (RAAK) study]. Unsupervised hierarchical clustering analysis on preserved cartilage transcriptome followed by clinical data integration was performed. Protein-protein interaction (PPI) followed by pathway enrichment analysis were done for genes significant differentially expressed between subgroups with interactions in the PPI network. RESULTS: Analysis of preserved samples (n = 56) resulted in two OA subtypes with n = 41 (cluster A) and n = 15 (cluster B) patients. The transcriptomic profile of cluster B cartilage, relative to cluster A (DE-AB genes) showed among others a pronounced upregulation of multiple genes involved in chemokine pathways. Nevertheless, upon investigating the OA pathophysiology in cluster B patients as reflected by differentially expressed genes between preserved and lesioned OA cartilage (DE-OA-B genes), the chemokine genes were significantly downregulated with OA pathophysiology. Upon integrating radiographic OA data, we showed that the OA phenotype among cluster B patients, relative to cluster A, may be characterized by higher joint space narrowing (JSN) scores and low osteophyte (OP) scores. CONCLUSION: Based on whole-transcriptome profiling, we identified two robust OA subtypes characterized by unique OA, pathophysiological processes in cartilage as well as a clinical phenotype. We advocate that further characterization, confirmation and clinical data integration is a prerequisite to allow for development of treatments towards personalized care with concurrently more effective treatment response.

Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis.

OBJECTIVE: Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA. METHODS: A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage. RESULTS: We report suggestive evidence (p<5×10-6) of association at 6 variants with OA endophenotypes that would have been missed by using presence of hip OA as the disease end point. For example, in the analysis of hip OA cases with superior maxJSN versus cases with non-superior maxJSN we detected association with a variant in the LRCH1 gene (rs754106, p=1.49×10-7, OR (95% CIs) 0.70 (0.61 to 0.80)). In the comparison of hypertrophic with non-hypertrophic OA the most significant variant was located between STT3B and GADL1 (rs6766414, p=3.13×10-6, OR (95% CIs) 1.45 (1.24 to 1.69)). Both of these associations were fully attenuated in non-stratified analyses of all hip OA cases versus population controls (p>0.05). STT3B was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10-4). CONCLUSIONS: Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity.

Automatic radiographic quantification of hand osteoarthritis; accuracy and sensitivity to change in joint space width in a phantom and cadaver study.

OBJECTIVE: To validate a newly developed quantification method that automatically detects and quantifies the joint space width (JSW) in hand radiographs. Repeatability, accuracy and sensitivity to changes in JSW were determined. The influence of joint location and joint shape on the measurements was tested. METHODS: A mechanical micrometer set-up was developed to define and adjust the true JSW in an acrylic phantom joint and in human cadaver-derived phalangeal joints. Radiographic measurements of the JSW were compared to the true JSW. Repeatability, systematic error (accuracy) and sensitivity (defined as the smallest detectable difference (SDD)) were determined. The influence of joint position on the JSW measurement was assessed by varying the location of the acrylic phantom on the X-ray detector with respect to the X-ray beam and the influence of joint shape was determined by using morphologically different human cadaver joints. RESULTS: The mean systematic error was 0.052 mm in the phantom joint and 0.210 mm in the cadaver experiment. In the phantom experiments, the repeatability was high (SDD = 0.028 mm), but differed slightly between joint locations (p = 0.046), and a change in JSW of 0.037 mm could be detected. Dependent of the joint shape in the cadaver hand, a change in JSW between 0.018 and 0.047 mm could be detected. CONCLUSIONS: The automatic quantification method is sensitive to small changes in JSW. Considering the published data of JSW decline in the normal and osteoarthritic population, the first signs of OA progression with this method can be detected within 1 or 2 years.

Localized development of knee osteoarthritis can be predicted from MR imaging findings a decade earlier.

PURPOSE: To define localized development of knee osteoarthritis (OA) that arises from anterior cruciate ligament (ACL) and meniscal injuries identified at magnetic resonance (MR) imaging performed a decade ago and the subsequent management of those findings in patients with subacute knee symptoms. MATERIALS AND METHODS: The present study was approved by local medical ethics review boards, and written informed consent was obtained. Three hundred twenty-six patients (mean age, 42 years; 108 female) from a previously reported series of 855 patients were followed up with regard to the effect of MR imaging-guided treatment for subacute knee problems. The mean follow-up period was 10 years. Initial findings and treatment were compared with the follow-up radiograph and 3.0-T MR image findings. Odds ratios (ORs), with corresponding 95% confidence intervals, were used to identify the effects between variables. RESULTS: Patients with ACL ruptures had an increased risk of developing joint space narrowing (JSN), cartilaginous defects, osteophytes, bone marrow lesions, and subchondral cysts medially or laterally (OR, 2.4-9.8). Patients with medial meniscal tears had an increased risk of developing JSN, cartilaginous defects, osteophytes, and bone marrow lesions medially (OR, 2.0-15.3). Patients with lateral meniscal tears had an increased risk of developing JSN, cartilaginous defects, osteophytes, bone marrow lesions, and subchondral cysts laterally (OR, 2.1-10.5). Meniscectomy had no effect on the risk of developing OA. CONCLUSION: Localized knee OA developed from risk factors identified from the findings of MR imaging performed a decade ago in patients with subacute knee symptoms and did not depend on the surgical treatment of those findings.

Genetic Contribution to the Development of Radiographic Knee Osteoarthritis in a Population Presenting with Nonacute Knee Symptoms a Decade Earlier.

This study examined the contribution of the osteoarthritis (OA) susceptibility genes ASPN, GDF5, DIO2, and the 7q22 region to the development of radiographic knee OA in patients with a mean age of 40.6 ± 7.9 years (standard deviation) and who suffered from nonacute knee complaints a decade earlier. Dose-response associations of four single nucleotide polymorphisms(SNPs) in the susceptibility genes were determined by comparing 36 patients who showed the development of OA on radiographs (Kellgren and Lawrence score ≥1) with 88 patients having normal cartilage with no development of OA on radiographs. Multivariate logistic regression analysis including the variables such as age, gender, body mass index, and reported knee trauma was performed. A dose-response association of DIO2 SNP rs225014: odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1-4.5 (P = 0.019) and GDF5 SNP rs143383: OR 2.0, 95% CI 1.1-3.8 (P = 0.031) was observed with knee OA development. The ASPN and 7q22 SNPs were not associated with OA development.

Identification of factors associated with the development of knee osteoarthritis in a young to middle-aged cohort of patients with knee complaints.

The objective of this study was to identify risk factors for knee osteoarthritis (OA) development in a young to middle-aged population with sub-acute knee complaints. This, in order to define high risk patients who may benefit from early preventive or future disease modifying therapies. Knee OA development visible on radiographs and MR in 319 patients (mean age 41.5 years) 10 years after sub-acute knee complaints and subjective knee function (KOOS score) was studied. Associations between OA development and age, gender, activity level, BMI, meniscal or anterior cruciate ligament (ACL) lesions, OA in first-degree relatives and radiographic hand OA were determined using multivariable logistic regression analysis. OA on radiographs and MR in the TFC is associated with increased age (OR: 1.10, 95 % 1.04-1.16 and OR: 1.07, 95 % 1.02-1.13). TFC OA on radiographs only is associated with ACL and/or meniscal lesions (OR: 5.01, 95 % 2.14-11.73), presence of hand OA (OR: 4.69, 95 % 1.35-16.32) and higher Tegner activity scores at baseline before the complaints (OR: 1.20, 95 % 1.01-1.43). The presence of OA in the TFC diagnosed only on MRI is associated with a family history of OA (OR: 2.44, 95 % 1.18-5.06) and a higher BMI (OR: 1.13, 95 % 1.04-1.23). OA in the PFC diagnosed on both radiographs and MR is associated with an increased age (OR: 1.06, 95 % 1.02-1.12 and OR: 1.05, 95 % 1.00-1.09). PFC OA diagnosed on radiographs only is associated with a higher BMI (OR: 1.12, 95 % 1.02-1.22). The presence of OA in the PFC diagnosed on MR only is associated with the presence of hand OA (OR: 3.39, 95 % 1.10-10.50). Compared to normal reference values, the study population had significantly lower KOOS scores in the different subscales. These results show that knee OA development in young to middle aged patients with a history of sub-acute knee complaints is associated with the presence of known risk factors for knee OA. OA is already visible on radiographs and MRI after 10 years. These high risk patients may benefit from adequate OA management early in life.