Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW ( P = 4.8 × 10 −10 ). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10 −11 . The SNP was also strongly associated with a 12% reduced risk for HOA ( P = 1 × 10 −4 ). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.

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IntroductionTo determine if structural bone parameters obtained from dual energy X-ray absorptiometry (DXA) contribute to the prediction of progression of hip osteoarthritis (OA) and to test if the difference between the most affected (OA) hip and the contralateral hip adds to this prediction.MethodsThe study group involves a prospective cohort of 189 patients that met the American College of Rheumatology (ARC) classification criteria for hip osteoarthritis. Progression was defined as 20% joint space narrowing or total hip replacement within a two years follow up. Software was developed to calculate geometrical aspects and bone mineral density (BMD) in different regions of interest of the proximal femur. Logistic regression was used to test if Kellgren and Lawrence (K-L) scores and DXA parameters can predict progression of OA. Models were compared using -2log likelihood tests, R2 Nagelkerke and areas under the Receiver Operator Characteristic curves, assessed using 10-fold cross validation.ResultsThe model that included the DXA variables was significantly better in predicting hip OA progression than the model with K-L score of the affected side alone (P < 0.01). The addition of the differences in DXA parameters between the most affected and contralateral hip in the superior part of the femoral head, trochanteric and intertrochanteric area further improved the prediction of progression (P < 0.05). K-L score of the affected side was still the most significant single variable in the models.ConclusionsDXA parameters can significantly contribute to the prediction of progression in patients with hip osteoarthritis. The analysis of the DXA differences between the hips of the patient represents a small but significant contribution to this prediction. These analyses show the importance of bone density changes in the etiology of OA.

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Purpose: Patello-femoral (PF) cartilage damage can cause severe knee pain and result in increasing disability. The purpose of this study was to identify factors associated with grade 4 defects of the patello-femoral joint. Methods: A cohort of 2601 patients (average age¼45, range, 18 to 83) who underwent knee arthroscopy for knee pathology were studied prospectively. All patients had complete demographic data, surgical data, WOMAC scores, and health status (SF12) collected at initial exam and stored in a data registry. Patients with chondral defects of the knee were included. Patients less than 18 years of age were excluded. Results: Grade 4 PF chondral defects were seen in 23% (586) of knees, with 6% (150) patellar (PAT) defects, 10% (267) trochlear groove (TG) defects and 6% (169) combined PAT and TG defects. 29% of patients with grade 4 PF chondral defects had medial compartment chondral defects, while 14% of patients with no PF chondral defect had medial compartment chondral defects (p<0.001). 20% of patients with PF chondral defects had lateral compartment chondral defects, while 12% of knees with no PF chondral defect had lateral compartment chondral defects. PF chondral defects were 3.0 [95%CI: 2.1 to 4.3] times more likely to be chronic injuries. Knees without PF defects were 20 [95%CI: 15.7 to 26.2] times more likely to have ligament injuries than knees with PF defects. Patients with grade 4 TG defects were older (51 vs 45) and had increased stiffness (how was stiffness determined?) compared to other patients (p<0.001). Patients with grade 4 PAT defects were older (52 vs 45; p<0.001) and had increased pain compared to other patients. Patients with diffuse grade 4 PAT defects had increased age, increased WOMAC (increased disability) and decreased Lysholm scores. Conclusions: This study confirms that grade 4 defects of the PF compartment are common. They often occur with chondral defects in other compartments; however, they are not associated with ligament or meniscus injuries. Patients with PF defects are older than patients with other cartilage damage, and patients with grade 4 diffuse defects of the patella suffer the most disability and loss of function. These data confirm the importance of new treatment strategies for chondral defects of the patellofemoral compartment, especially since patellar resurfacing remains controversial.