Mitochondrial DNA haplogroups influence the risk of incident knee osteoarthritis in OAI and CHECK cohorts. A meta-analysis and functional study.

OBJECTIVE: To evaluate the influence of the mitochondrial DNA (mtDNA) haplogroups in the risk of incident knee osteoarthritis (OA) and to explain the functional consequences of this association to identify potential diagnostic biomarkers and therapeutic targets. METHODS: Two prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 2579 subjects of the incidence subcohort, and the cohort hip and cohort knee (CHECK) included 635, both with 8-year follow-up. The analysis included the association of mtDNA haplogroups with the rate of incident knee OA in subjects from both cohorts followed by a subsequent meta-analysis. Transmitochondrial cybrids harbouring haplogroup J or H were constructed to detect differences between them in relation to physiological features including specific mitochondrial metabolic parameters, reactive oxygen species production, oxidative stress and apoptosis. RESULTS: Compared with H, the haplogroup J associates with decreased risk of incident knee OA in subjects from OAI (HR=0.680; 95% CI 0.470 to 0.968; p<0.05) and CHECK (HR=0.728; 95% CI 0.469 to 0.998; p<0.05). The subsequent meta-analysis including 3214 cases showed that the haplogroup J associates with a lower risk of incident knee OA (HR=0.702; 95% CI 0.541 to 0.912; p=0.008). J cybrids show a lower free radical production, higher cell survival under oxidative stress conditions, lower grade of apoptosis as well as lower expression of the mitochondrially related pro-apoptotic gene BCL2 binding component 3 (BBC3). In addition, J cybrids also show a lower mitochondrial respiration and glycolysis leading to decreased ATP production. CONCLUSIONS: The physiological effects of the haplogroup J are beneficial to have a lower rate of incident knee OA over time. Potential drugs to treat OA could focus on emulating the mitochondrial behaviour of this haplogroup.

A replication study and meta-analysis of mitochondrial DNA variants in the radiographic progression of knee osteoarthritis.

OBJECTIVE: To conduct a replication study and meta-analysis involving the study of mtDNA variants in the radiographic progression of OA in different cohorts worldwide, including Cohort Hip and Cohort Knee (CHECK), the OA Initiative and a cohort from Spain. METHODS: The influence of the haplogroups in the rate of radiographic progression at 96 months in 431 subjects from CHECK was assessed in terms of Kellgren and Lawrence (KL) grade. Progression was defined as a change from KL ⩾ 1 at baseline to any higher grade during the follow-up. Extended Cox proportional hazard models were used to analyse the influence of mtDNA variants in the rate of radiographic knee OA progression. A subsequent meta-analysis of 1603 subjects following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted to combine the data of individual studies. A sensitivity analysis was performed to validate the stability of the results. RESULTS: CHECK subjects carrying the haplogroup T showed the lowest rate of radiographic knee OA progression [hazard ratio (HR) 0.645 (95% CI 0.419, 0.978); P < 0.05]. When pooled, subjects within the superhaplogroup JT showed the same trend [HR 0.707 (95% CI 0.501, 0.965); P < 0.05]. BMI [HR 1.046 (95% CI 1.018, 1.073); P < 0.05] and bilateral OA [HR 2.266 (95% CI 1.733, 2.954); P < 0.05] at baseline are risk factors for radiographic knee OA progression as well. In the meta-analysis there was a reduced rate of radiographic progression in subjects with haplogroup T [HR 0.612 (95% CI 0.454, 0.824); P = 0.001] or in the superhaplogroup JT [HR 0.765 (95% CI 0.624, 0.938); P = 0.009]. Sensitivity analysis revealed that the results were robust. CONCLUSION: The mtDNA variants in the superhaplogroup JT associate with a reduced rate of radiographic OA progression. The mtDNA polymorphisms in the superhaplogroup JT emerge as potential complementary genetic biomarkers for disease progression.

Higher Synovial Immunohistochemistry Reactivity of IL-17A, Dkk1, and TGF-ß1 in Patients with Early Psoriatic Arthritis and Rheumatoid Arthritis Could Predict the Use of Biologics.

BACKGROUND: Delay in diagnosis and therapy in patients with arthritis commonly leads to progressive articular damage. The study aimed to investigate the immunohistochemical reactivity of synovial cytokines associated with inflammation and the bone erosives/neoformatives processes among individuals diagnosed with psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), and radiographic axial spondyloarthritis (r-axSpA), with the intention of identifying potential biomarkers. METHODS: Specimens were collected from the inflamed knee joints of patients referred for arthroscopic procedures, and the synovial tissue (ST) was prepared for quantifying protein expression through immunohistochemical analysis (% expressed in Ratio_Area-Intensity) for TGF-ß1, IL-17A, Dkk1, BMP2, BMP4, and Wnt5b. The collected data underwent thorough analysis and examination of their predictive capabilities utilising receiver operating characteristic (ROC) curves. RESULTS: Valid synovial tissue samples were acquired from 40 patients for IHC quantification analysis. Initially, these patients had not undergone treatment with biologics. However, after 5 years, 4 out of 13 patients diagnosed with PsA and two out of nine patients diagnosed with RA had commenced biologic treatments. Individuals with early PsA who received subsequent biologic treatment exhibited significantly elevated IHC reactivity in ST for TGF-ß1 (p = 0.015). Additionally, patients with both PsA and RA who underwent biologic therapy displayed increased IHC reactivity for IL-17A (p = 0.016), TGF-ß1 (p = 0.009), and Dkk1 (p = 0.042). ROC curve analysis of IHC reactivity for TGF-ß1, Dkk1, and IL-17A in the synovial seems to predict future treatment with biologics in the next 5 years with the area under the curve (AUC) of a combined sum of the three values: AUC: 0.828 (95% CI: 0.689-0.968; p 0.005) S 75% E 84.4%. CONCLUSIONS: Higher synovial immunohistochemistry reactivity of IL-17A, Dkk1, and TGF-ß1 in patients with early psoriatic arthritis and rheumatoid arthritis may serve as potential indicators for predicting the necessity of utilising biologic treatments.

PROCOAC (PROspective COhort of A Coruña) description: Spanish prospective cohort to study osteoarthritis.

INTRODUCTION AND OBJECTIVE: The use of well characterized osteoarthritis (OA) cohorts is mandatory for the study and knowledge of this disease. Currently, there is no prospective cohort in this pathology in Spain. The objective of this work is to describe the first osteoarthritis cohort in Spain, PROCOAC (Cohort PROspectiva de A Coruña). METHODS: The Unit of Rheumatology of the University Hospital of A Coruña started a prospective follow-up study in 2006. The patient inclusion criteria were: I) Patients older than 55 years who underwent an abdominal x-ray to study both hips II) Patients diagnosed with radiographic hand OA according to ACR criteria III) Patients diagnosed with radiographic knee or hip OA according to ACR criteria. Follow-up was performed every two years collecting clinical, analytical, genetic and radiographic information. RESULTS: The cohort consists of 937 patients, 873 have radiographic knee OA, 783 hip OA and 679 hand OA. The mean age of the population is 63.9±8.9 years and the average BMI is 29.6±5.1. More than half of the population has high blood pressure and 17% diabetes. The predominant osteoarthritis in the hand is nodular (78.1%), followed by trapeziometacarpal (55.3%) and erosive (18.4%). Twenty-one point four percent and 43.1% are healthy at knee and hip level respectively; observing a grade 1 in 26% and 37%; a grade 2 in 26.7% and 11.5%; a grade 3 in 14.9% and 4%; and a grade 4 in 9.4% and 3.7% respectively. Of the population, 44.1% has only 1 joint affected, 39.9% has 2 and 13.4% has 3 joints affected. Age (OR=1.11; p<.001), BMI (OR=1.11; p=.002) and total WOMAC (OR=1.03; p=.005) are the only risk factors if we compare the involvement of a single location versus three. A discrepancy between pain and radiographic damage at the joint level was also detected in patients with KL≤2 grade, and therefore a significantly higher percentage of patients with knee OA experienced pain (66.1%) compared to patients with OA hip (21.1%) (p<.001). CONCLUSIONS: The PROCOAC cohort is an instrument that allows studies of incidence and progression in hand, knee and hip OA; as well as determining factors that are associated with the different OA phenotypes.

Reduced Levels of H2S in Diabetes-Associated Osteoarthritis Are Linked to Hyperglycaemia, Nrf-2/HO-1 Signalling Downregulation and Chondrocyte Dysfunction.

Different findings indicate that type 2 diabetes is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Changes in the balance of hydrogen sulphide (H2S) are thought to play an important role in the pathogenesis of diabetes and its complications, although its role is still controversial. In this study, we examined the modulation of H2S levels in serum and chondrocytes from OA diabetic (DB) and non-diabetic (non-DB) patients and in cells under glucose stress, in order to elucidate whether impairment in H2S-mediated signalling could participate in the onset of DB-related OA. Here, we identified a reduction in H2S synthesis in the cartilage from OA-DB patients and in cells under glucose stress, which is associated with hyperglycaemia-mediated dysregulation of chondrocyte metabolism. In addition, our results indicate that H2S is an inductor of the Nrf-2/HO-1 signalling pathway in cartilage, but is also a downstream target of Nrf-2 transcriptional activity. Thereby, impairment of the H2S/Nrf-2 axis under glucose stress or DB triggers chondrocyte catabolic responses, favouring the disruption of cartilage homeostasis that characterizes OA pathology. Finally, our findings highlight the benefits of the use of exogeneous sources of H2S in the treatment of DB-OA patients, and warrant future clinical studies.

PROCOAC (PROspective COhort of A Coruña) description: Spanish prospective cohort to study osteoarthritis. / Descripción de la cohorte PROCOAC (PROspective COhort of A Coruña): Cohorte prospectiva española para el estudio de la osteoartritis.

INTRODUCTION AND OBJECTIVE: The use of well characterized osteoarthritis cohorts is mandatory for the study and knowledge of this disease. Currently, there is no prospective cohort in this pathology in Spain. The objective of this work is to describe the first osteoarthritis cohort in Spain, PROCOAC (Cohort PROspectiva de A Coruña). METHODS: The Unit of Rheumatology of the University Hospital of A Coruña started a prospective follow-up study in 2006. The patient inclusion criteria were: a) patients older than 55 years who underwent an abdominal x-ray to study both hips; b) patients diagnosed with radiographic hand osteoarthritis according to ACR criteria; c) patients diagnosed with radiographic knee or hip osteoarthritis according to ACR criteria. Follow-up was performed every 2years collecting clinical, analytical, genetic and radiographic information. RESULTS: The cohort consists of 937 patients, 873 have radiographic knee osteoarthritis, 783 hip osteoarthritis and 679 hand osteoarthritis. The mean age of the population is 63.9±8.9 years and the average BMI is 29.6±5.1. More than half of the population has high blood pressure and 17% diabetes. The predominant osteoarthritis in the hand is nodular (78.1%), followed by trapeziometacarpal (55.3%) and erosive (18.4%). Of them, 21.4% and 43.1% are healthy at knee and hip level respectively; observing a grade 1 in 26% and 37%; a grade 2 in 26.7% and 11.5%; a grade 3 in 14.9% and 4%; and a grade 4 in 9.4% and 3.7%, respectively. Of the population, 44.1% has only one joint affected, 39.9% has 2 and 13.4% has 3 joints affected. Age (OR=1.11; P <.001), BMI (OR=1.11; P=.002) and total WOMAC (OR=1.03; P=.005) are the only risk factors if we compare the involvement of a single location versus 3. A discrepancy between pain and radiographic damage at the joint level was also detected in patients with KL ≤ 2 grade, and therefore a significantly higher percentage of patients with knee osteoarthritis experienced pain (66.1%) compared to patients with osteoarthritis hip (21.1%) (P<.001). CONCLUSIONS: The PROCOAC cohort is an instrument that allows studies of incidence and progression in hand, knee and hip osteoarthritis; as well as determining factors that are associated with the different osteoarthritis phenotypes.

Descripción de la cohorte PROCOAC (PROspective COhort of A Coruña): Cohorte prospectiva española para el estudio de la osteoartritis / PROCOAC (PROspective COhort of A Coruña) description: Spanish prospective cohort to study osteoarthritis

Introducción y objetivo: El uso de cohortes de osteoartritis bien caracterizadas es obligatorio para estudiar y profundizar en el conocimiento en esta enfermedad. En España no existe actualmente ninguna cohorte prospectiva en este ámbito; por ello, el objetivo de este trabajo es describir la primera cohorte de osteoartritis en España: la PROCOAC (PROspective COhort of A Coruña). Material y métodos: El Servicio de Reumatología del Hospital Universitario de La Coruña inició un estudio de seguimiento prospectivo en el año 2006. Los criterios de inclusión fueron: a) pacientes mayores de 55 años a los que se les realizó una radiografía abdominal que permitiese estudiar ambas caderas; b) pacientes diagnosticados de osteoartritis radiográfica de mano según los criterios ACR; c) pacientes diagnosticados de osteoartritis radiográfica de rodilla o cadera según los criterios ACR. Se realizó seguimiento cada 2años y se recogió información clínica, analítica, genética y radiográfica. Resultados: La cohorte consta de 937 individuos; 873 tienen osteoartritis radiográfica de rodilla, 783 de cadera y 679 de mano. La edad media de la población es 63,9±8,9 años y el IMC promedio de 29,6±5,1. Más de la mitad de la población tiene hipertensión arterial y el 17%, diabetes. La osteoartritis predominante en la mano es la nodular (78,1%), seguida de la rizartrosis (55,3%) y la erosiva (18,4%). El 21,4% y el 43,1% tienen sanas la rodilla y la cadera, respectivamente. Se observa un grado 1 en el 26% y 37%; un grado 2 en el 26,7% y 11,5%; un grado 3 en el 14,9% y 4%; y un grado 4 en el 9,4% y 3,7%, respectivamente. El 44,1% de la población tiene una articulación afectada, el 39,9% tiene 2 y el 13,4% tiene las 3 articulaciones afectadas. La edad (OR=1,11; p<0,001), el IMC (OR=1,11; p=0,002) y el WOMAC total (OR=1,03; p=0,005) son los únicos factores de riesgo si comparamos la afectación de una sola ubicación frente a 3.(AU)

Introduction and objective: The use of well characterized osteoarthritis cohorts is mandatory for the study and knowledge of this disease. Currently, there is no prospective cohort in this pathology in Spain. The objective of this work is to describe the first osteoarthritis cohort in Spain, PROCOAC (Cohort PROspectiva de A Coruña). Methods: The Unit of Rheumatology of the University Hospital of A Coruña started a prospective follow-up study in 2006. The patient inclusion criteria were: a) patients older than 55 years who underwent an abdominal x-ray to study both hips; b) patients diagnosed with radiographic hand osteoarthritis according to ACR criteria; c) patients diagnosed with radiographic knee or hip osteoarthritis according to ACR criteria. Follow-up was performed every 2years collecting clinical, analytical, genetic and radiographic information. Results: The cohort consists of 937 patients, 873 have radiographic knee osteoarthritis, 783 hip osteoarthritis and 679 hand osteoarthritis. The mean age of the population is 63.9±8.9 years and the average BMI is 29.6±5.1. More than half of the population has high blood pressure and 17% diabetes. The predominant osteoarthritis in the hand is nodular (78.1%), followed by trapeziometacarpal (55.3%) and erosive (18.4%). Of them, 21.4% and 43.1% are healthy at knee and hip level respectively; observing a grade 1 in 26% and 37%; a grade 2 in 26.7% and 11.5%; a grade 3 in 14.9% and 4%; and a grade 4 in 9.4% and 3.7%, respectively. Of the population, 44.1% has only one joint affected, 39.9% has 2 and 13.4% has 3 joints affected. Age (OR=1.11; P <.001), BMI (OR=1.11; P=.002) and total WOMAC (OR=1.03; P=.005) are the only risk factors if we compare the involvement of a single location versus 3.(AU)