Metabolic syndrome is not associated with erosive hand osteoarthritis: a cross-sectional study using data from the PROCOAC cohort.

To delineate the phenotype of erosive hand osteoarthritis (EHOA) in a Spanish population and assess its correlation with metabolic syndrome. We conducted a cross-sectional study using baseline data from the Prospective Cohort of Osteoarthritis from A Coruña (PROCOAC). Demographic and clinical variables, obtained through questionnaires, clinical examinations, and patient analytics, were compared among individuals with hand OA, with and without EHOA. We performed appropriate univariate and multivariate stepwise regression analyses using SPSS v28. Among 1039 subjects diagnosed with hand OA, 303 exhibited EHOA. Multivariate logistic regression analysis revealed associations with inflamed joints, nodular hand OA, and total AUSCAN. Furthermore, the association with a lower prevalence of knee OA remained significant. The influence of metabolic syndrome (MetS) on EHOA patients was analyzed by including MetS as a covariate in the model. It was observed that MetS does not significantly impact the presence of EHOA, maintaining the effect size of other factors. In conclusion, in the PROCOAC cohort, EHOA is associated with nodular hand OA, inflammatory hand OA, and a higher total AUSCAN. However, EHOA is linked to a lower prevalence of knee OA. Importantly, in our cohort, no relationship was found between EHOA and MetS.

Mitonuclear epistasis involving TP63 and haplogroup Uk: Risk of rapid progression of knee OA in patients from the OAI.

OBJECTIVE: To investigate genetic interactions between mitochondrial deoxyribonucleic acid (mtDNA) haplogroups and nuclear single nucleotide polymorphisms (nSNPs) to analyze their impact on the development of the rapid progression of knee osteoarthritis (OA). DESIGN: A total of 1095 subjects from the Osteoarthritis Initiative, with a follow-up time of at least 48-months, were included. Appropriate statistical approaches were performed, including generalized estimating equations adjusting for age, gender, body mass index, contralateral knee OA, Western Ontario and McMaster Universities Osteoarthritis Index pain, previous injury in target knee and the presence of the mtDNA variant m.16519C. Additional genomic data consisted in the genotyping of Caucasian mtDNA haplogroups and eight nSNPs previously associated with the risk of knee OA in robust genome-wide association studies. RESULTS: The simultaneous presence of the G allele of rs12107036 at TP63 and the haplogroup Uk significantly increases the risk of a rapid progression of knee OA (odds ratio = 1.670; 95% confidence interval [CI]: 1.031-2.706; adjusted p-value = 0.027). The assessment of the population attributable fraction showed that the highest proportion of rapid progressors was under the simultaneous presence of the G allele of rs12107036 and the haplogroup Uk (23.4%) (95%CI: 7.89-38.9; p-value < 0.05). The area under the curve of the cross-validation model (0.730) was very similar to the obtained for the predictive model (0.735). A nomogram was constructed to help clinicians to perform clinical trials or epidemiologic studies. CONCLUSIONS: This study demonstrates the existence of a mitonuclear epistasis in OA, providing new mechanisms by which nuclear and mitochondrial variation influence the susceptibility to develop different OA phenotypes.

A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis.

OBJECTIVES: To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids. METHODS: Three prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 1095 subjects, the Cohort Hip and Cohort Knee included 373 and 326 came from the PROspective Cohort of Osteoarthritis from A Coruña. mtDNA variants were screened in an initial subset of 450 subjects from the OAI by in-depth sequencing of mtDNA. A meta-analysis of the three cohorts was performed. A model of cybrids was constructed to study the functional consequences of harbouring the risk mtDNA variant by assessing: mtDNA copy number, mitochondrial biosynthesis, mitochondrial fission and fusion, mitochondrial reactive oxygen species (ROS), oxidative stress, autophagy and a whole transcriptome analysis by RNA-sequencing. RESULTS: mtDNA variant m.16519C is over-represented in rapid progressors (combined OR 1.546; 95% CI 1.163 to 2.054; p=0.0027). Cybrids with this variant show increased mtDNA copy number and decreased mitochondrial biosynthesis; they produce higher amounts of mitochondrial ROS, are less resistant to oxidative stress, show a lower expression of the mitochondrial fission-related gene fission mitochondrial 1 and an impairment of autophagic flux. In addition, its presence modulates the transcriptome of cybrids, especially in terms of inflammation, where interleukin 6 emerges as one of the most differentially expressed genes. CONCLUSIONS: The presence of the mtDNA variant m.16519C increases the risk of rapid progression of knee OA. Among the most modulated biological processes associated with this variant, inflammation and negative regulation of cellular process stand out. The design of therapies based on the maintenance of mitochondrial function is recommended.

Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect.

OBJECTIVES: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. METHODS: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. RESULTS: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4×10-14) and rs11243284 (6p24.3, OR=1.35, p=4.2×10-11) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1×10-18), and rs1800801 (MGP, OR=1.37, p=3.6×10-13) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. CONCLUSIONS: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints.

Single nucleotide polymorphism genes and mitochondrial DNA haplogroups as biomarkers for early prediction of knee osteoarthritis structural progressors: use of supervised machine learning classifiers.

BACKGROUND: Knee osteoarthritis is the most prevalent chronic musculoskeletal debilitating disease. Current treatments are only symptomatic, and to improve this, we need a robust prediction model to stratify patients at an early stage according to the risk of joint structure disease progression. Some genetic factors, including single nucleotide polymorphism (SNP) genes and mitochondrial (mt)DNA haplogroups/clusters, have been linked to this disease. For the first time, we aim to determine, by using machine learning, whether some SNP genes and mtDNA haplogroups/clusters alone or combined could predict early knee osteoarthritis structural progressors. METHODS: Participants (901) were first classified for the probability of being structural progressors. Genotyping included SNP genes TP63, FTO, GNL3, DUS4L, GDF5, SUPT3H, MCF2L, and TGFA; mtDNA haplogroups H, J, T, Uk, and others; and clusters HV, TJ, KU, and C-others. They were considered for prediction with major risk factors of osteoarthritis, namely, age and body mass index (BMI). Seven supervised machine learning methodologies were evaluated. The support vector machine was used to generate gender-based models. The best input combination was assessed using sensitivity and synergy analyses. Validation was performed using tenfold cross-validation and an external cohort (TASOAC). RESULTS: From 277 models, two were defined. Both used age and BMI in addition for the first one of the SNP genes TP63, DUS4L, GDF5, and FTO with an accuracy of 85.0%; the second profits from the association of mtDNA haplogroups and SNP genes FTO and SUPT3H with 82.5% accuracy. The highest impact was associated with the haplogroup H, the presence of CT alleles for rs8044769 at FTO, and the absence of AA for rs10948172 at SUPT3H. Validation accuracy with the cross-validation (about 95%) and the external cohort (90.5%, 85.7%, respectively) was excellent for both models. CONCLUSIONS: This study introduces a novel source of decision support in precision medicine in which, for the first time, two models were developed consisting of (i) age, BMI, TP63, DUS4L, GDF5, and FTO and (ii) the optimum one as it has one less variable: age, BMI, mtDNA haplogroup, FTO, and SUPT3H. Such a framework is translational and would benefit patients at risk of structural progressive knee osteoarthritis.

mtDNA variability determines spontaneous joint aging damage in a conplastic mouse model.

Mitochondria and mtDNA variations contribute to specific aspects of the aging process. Here, we aimed to investigate the influence of mtDNA variation on joint damage in a model of aging using conplastic mice. A conplastic (BL/6NZB) mouse strain was developed with the C57BL/6JOlaHsd nuclear genome and NZB/OlaHsd mtDNA, for comparison with the original C57BL/6JOlaHsd strain (BL/6C57). Conplastic (BL/6NZB) and BL/6C57 mice were sacrificed at 25, 75, and 90 weeks of age. Hind knee joints were processed for histological analysis and joint pathology graded using the Mankin scoring system. By immunohistochemistry, cartilage expression of markers of autophagy (LC3, Beclin-1, and P62) and markers of senescence (MMP13, beta-Galactosidase, and p16) and proliferation (Ki67) were analyzed. We also measured the expression of 8-oxo-dG and cleaved caspase-3. Conplastic (BL/6NZB) mice presented lower Mankin scores at 25, 75, and 90 weeks of age, higher expression of LC3 and Beclin-1 and lower of P62 in cartilage than the original strain. Moreover, the downregulation of MMP13, beta-Galactosidase, and p16 was detected in cartilage from conplastic (BL/6NZB) mice, whereas higher Ki67 levels were detected in these mice. Finally, control BL/6C57 mice showed higher cartilage expression of 8-oxo-dG and cleaved caspase-3 than conplastic (BL/6NZB) mice. This study demonstrates that mtDNA genetic manipulation ameliorates joint aging damage in a conplastic mouse model, suggesting that mtDNA variability is a prognostic factor for aging-related osteoarthritis (OA) and that modulation of mitochondrial oxidative phosphorylation (OXPHOS) could be a novel therapeutic target for treating OA associated with aging.

mtDNA haplogroup A enhances the effect of obesity on the risk of knee OA in a Mexican population.

To evaluate the influence of mitochondrial DNA haplogroups on the risk of knee OA in terms of their interaction with obesity, in a population from Mexico. Samples were obtained from (n = 353) knee OA patients (KL grade ≥ I) and (n = 364) healthy controls (KL grade = 0) from Mexico city and Torreon (Mexico). Both Caucasian and Amerindian mtDNA haplogroups were assigned by single base extension assay. A set of clinical and demographic variables, including obesity status, were considered to perform appropriate statistical approaches, including chi-square contingency tables, regression models and interaction analyses. To ensure the robustness of the predictive model, a statistical cross-validation strategy of B = 1000 iterations was used. All the analyses were performed using boot, GmAMisc and epiR package from R software v4.0.2 and SPSS software v24. The frequency distribution of the mtDNA haplogroups between OA patients and healthy controls for obese and non-obese groups showed the haplogroup A as significantly over-represented in knee OA patients within the obese group (OR 2.23; 95% CI 1.22-4.05; p-value = 0.008). The subsequent logistic regression analysis, including as covariate the interaction between obesity and mtDNA haplogroup A, supported the significant association of this interaction (OR 2.57; 95% CI 1.24-5.32; p-value = 0.011). The statistical cross-validation strategy confirmed the robustness of the regression model. The data presented here indicate a link between obesity in knee OA patients and mtDNA haplogroup A.

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.

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)

Is osteoarthritis a mitochondrial disease? What is the evidence.

PROPOSE OF REVIEW: To summarize the evidence that suggests that osteoarthritis (OA) is a mitochondrial disease. RECENT FINDINGS: Mitochondrial dysfunction together with mtDNA damage could contribute to cartilage degradation via several processes such as: (1) increased apoptosis; (2) decreased autophagy; (3) enhanced inflammatory response; (4) telomere shortening and increased senescence chondrocytes; (5) decreased mitochondrial biogenesis and mitophagy; (6) increased cartilage catabolism; (7) increased mitochondrial fusion leading to further reactive oxygen species production; and (8) impaired metabolic flexibility. SUMMARY: Mitochondria play an important role in some events involved in the pathogenesis of OA, such as energy production, the generation of reactive oxygen and nitrogen species, apoptosis, authophagy, senescence and inflammation. The regulation of these processes in the cartilage is at least partially controlled by retrograde regulation from mitochondria and mitochondrial genetic variation. Retrograde regulation through mitochondrial haplogroups exerts a signaling control over the nuclear epigenome, which leads to the modulation of nuclear genes, cellular functions and development of OA. All these data suggest that OA could be considered a mitochondrial disease as well as other complex chronic disease as cancer, cardiovascular and neurologic diseases.

Association of accelerated dynamics of telomere sequence loss in peripheral blood leukocytes with incident knee osteoarthritis in Osteoarthritis Initiative cohort.

Osteoarthritis (OA) is a chronic degenerative joint disease, being the main cause of laboral inability. Decreased telomere size in peripheral blood leukocytes (PBL) has been correlated with age-related pathologies, like knee OA. In a dynamic approach, telomere-qPCR was performed to evaluate the relative percentage of PBL telomere loss after a 6-year follow-up, in 281 subjects from the prospective osteoarthritis initiative (OAI) cohort. A radiological Kellgren-Lawrence (KL) grade ≥ 2 was indicative of knee OA. Individuals with knee OA at recruitment (n = 144) showed a higher PBL telomere loss after 6 years than those without knee OA at baseline (n = 137; p = 0.018). Moreover, individuals that developed knee OA during the follow-up (n = 39) exhibited a higher telomere loss compared to those that remained without OA (n = 98; p < 0.001). Logistic regression analysis showed that PBLs telomere loss was not significantly associated with knee OA at recruitment, but behaves as an independent risk factor associated with incidence after follow-up (OR: 1.043; p = 0.041), together with maximum KL grade (OR: 3.627; p = 0.011), body mass index-BMI (OR: 1.252; p < 0.001) and WOMAC-index (OR: 1.247; p = 0.021), at recruitment. The telomere decay in PBLs is faster in individuals with incident knee OA, possibly reflecting a systemic-global accelerated aging that enhances the cartilage degeneration.

Oleate Prevents Palmitate-Induced Mitochondrial Dysfunction in Chondrocytes.

The association between obesity and osteoarthritis (OA) in joints not subjected to mechanical overload, together with the relationship between OA and metabolic syndrome, suggests that there are systemic factors related to metabolic disorders that are involved in the metabolic phenotype of OA. The aim of this work is study the effects of palmitate and oleate on cellular metabolism in an "in vitro" model of human chondrocytes. The TC28a2 chondrocyte cell line was used to analyze the effect of palmitate and oleate on mitochondrial and glycolytic function, Adenosine triphosphate (ATP) production and lipid droplets accumulation. Palmitate, but not oleate, produces mitochondrial dysfunction observed with a lower coupling efficiency, maximal respiration and spare respiratory capacity. Glycolytic function showed lower rates both glycolytic capacity and glycolytic reserve when cells were incubated with fatty acids (FAs). The production rate of total and mitochondrial ATP showed lower values in chondrocytes incubated with palmitic acid (PA). The formation of lipid droplets increased in FA conditions, being significantly higher when the cells were incubated with oleic acid (OL). These results may help explain, at least in part, the close relationship of metabolic pathologies with OA, as well as help to elucidate some of the factors that can define a metabolic phenotype in OA.

Design of a digital-PCR assay to quantify fragmented human mitochondrial DNA.

Digital PCR (dPCR) has been adapted to quantify the proportion of mitochondrial DNA (mtDNA) molecules without and with double-strand DNA breaks (DSBs). This is based on a break-apart approach of two differentially labeled target sequences distantly located in the circular DNA molecule. When the two targets amplify in separated reaction partitions, the original mtDNA molecule should be fragmented by two DSBs at least, each in a different segment between targets. When both targets amplify in the same partition, it must correspond to a circular or linear mtDNA molecule. These two possibilities may be distinguished through a restriction endonuclease (RE) induced unique DSB within a DNA segment between the targets. After RE-digestion, separation of both target signals in different partitions must indicate the presence of a previous linear mtDNA molecule. Otherwise, joint amplification in the same partition would correspond to an initial circular mtDNA that has been linearized by the endonuclease. The procedure was validated by assaying different proportions of mtDNA fragmented by in vitro digestion with REs, evidencing a perfect accordance between the expected theoretical values and dPCR quantification. Samples from peripheral blood cells, cellular and extracellular DNA from the U2OS cell line, as well as cells incubated with ethidium bromide to induce mtDNA depletion, were evaluated. The technique may be of interest to complement the studies of mtDNA in relation to aging and human disease, as well as to assess possible adverse effects of certain drugs that could be related to affectation of mtDNA.

Mitochondrial DNA impact on joint damaged process in a conplastic mouse model after being surgically induced with osteoarthritis.

It has been suggested that mitochondrial dysfunction and mtDNA variations may contribute to osteoarthritis (OA) pathogenesis. However, the causative link to support this claim is lacking. Here, we surgically-induced OA in conplastic mice in order to evaluate the functional consequences of mtDNA haplotypes in their joint degeneration. BL/6NZB strain was developed with C57BL/6JOlaHsd nuclear genome and NZB/OlaHsdmtDNA while BL/6C57, which is the original, was developed with C57BL/6JOlaHsd nuclear genome and C57/OlaHsdmtDNA for comparison. The surgical DMM OA model was induced in both strains. Their knees were processed and examined for histopathological changes. Cartilage expression of markers of autophagy, apoptosis, oxidative stress and senescence were also analyzed by immunohistochemistry. The joints of BL/6NZB mice that were operated presented more cellularity together with a reduced OARSI histopathology score, subchondral bone, menisci score and synovitis compared to those of BL/6C57 mice. This was accompanied with higher autophagy and a lower apoptosis in the cartilage of BL/6NZB mice that were operated. Therefore, the study demonstrates the functional impact of non-pathological variants of mtDNA on OA process using a surgically-induced OA model. Conplastic (BL/6NZB ) mice develop less severe OA compared to the BL/6C57original strain. These findings demonstrate that mitochondria and mtDNA are critical targets for potential novel therapeutic approaches to treat osteoarthritis.

Mitochondrial DNA from osteoarthritic patients drives functional impairment of mitochondrial activity: a study on transmitochondrial cybrids.

With the redefinition of osteoarthritis (OA) and the understanding that the joint behaves as an organ, OA is now considered a systemic illness with a low grade of chronic inflammation. Mitochondrial dysfunction is well documented in OA and has the capacity to alter chondrocyte and synoviocyte function. Transmitochondrial cybrids are suggested as a useful cellular model to study mitochondrial biology in vitro, as they carry different mitochondrial variants with the same nuclear background. The aim of this work was to study mitochondrial and metabolic function of cybrids with mitochondrial DNA from healthy (N) and OA donors. In this work, the authors demonstrate that cybrids from OA patients behave differently from cybrids from N donors in several mitochondrial parameters. Furthermore, OA cybrids behave similarly to OA chondrocytes. These results enhance our understanding of the role of mitochondria in the degeneration process of OA and present cybrids as a useful model to study OA pathogenesis.

Relationship Between the Dynamics of Telomere Loss in Peripheral Blood Leukocytes From Knee Osteoarthritis Patients and Mitochondrial DNA Haplogroups.

OBJECTIVE: To evaluate the evolution of telomere length from peripheral blood leukocytes (PBLs) in subjects from the Osteoarthritis Initiative (OAI) cohort in relation to the incidence of osteoarthritis (OA), and to explore its possible interactive influence with the mitochondrial DNA (mtDNA) haplogroup. METHODS: Dynamics of telomere sequence loss were quantified in PBLs from initially healthy individuals (without symptoms or radiological signs), 78 carrying the mtDNA cluster HV, and 47 with cluster JT, from the OAI, during a 72-month follow-up period. The incidence of knee OA during this period (n = 39) was radiographically established when Kellgren-Lawrence (KL) score increased from < 2 at recruitment, to ≥ 2 at the end of 72 months of follow-up. Multivariate analysis using binary logistic regression was performed to assess PBL telomere loss and mtDNA haplogroups as associated risk factors of incidence of knee OA. RESULTS: Carriers of cluster HV showed knee OA incidence twice that of the JT carriers (n = 30 vs 9). The rate of PBL telomere loss was higher in cluster HV carriers and in individuals with incident knee OA. Multivariate analysis showed that the dynamics of PBL telomere shortening can be a consistent risk marker of knee OA incidence. Subjects with nonincident knee OA showed a slower telomere loss than those with incident knee OA; the difference was more significant in carriers of cluster JT than in HV. CONCLUSION: An increased rate of telomere loss in PBLs may reflect a systemic accelerated senescence phenotype that could be potentiated by the mitochondrial function, increasing the susceptibility of developing knee OA.

Genetic biomarkers in osteoarthritis: a quick overview.

Osteoarthritis (OA) is a chronic musculoskeletal disease with a polygenic and heterogeneous nature. In addition, when clinical manifestations appear, the evolution of the disease is usually already irreversible. Therefore, the efforts on OA research are focused mainly on the discovery of therapeutic targets and reliable biomarkers that permit the early identification of different OA-related parameters such as diagnosis, prognosis, or phenotype identification. To date, potential candidate protein biomarkers have been associated with different aspects of the disease; however, there is currently no gold standard. In this sense, genomic data could act as complementary biomarkers of diagnosis and prognosis or even help to identify therapeutic targets of the disease. In this review, we will describe the most recent advances in genetic biomarkers in OA over the past three years.

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.

Impaired Metabolic Flexibility in the Osteoarthritis Process: A Study on Transmitochondrial Cybrids.

Osteoarthritis (OA) is the most frequent joint disease; however, the etiopathogenesis is still unclear. Chondrocytes rely primarily on glycolysis to meet cellular energy demand, but studies implicate impaired mitochondrial function in OA pathogenesis. The relationship between mitochondrial dysfunction and OA has been established. The aim of the study was to examine the differences in glucose and Fatty Acids (FA) metabolism, especially with regards to metabolic flexibility, in cybrids from healthy (N) or OA donors. Glucose and FA metabolism were studied using D-[14C(U)]glucose and [1-14C]oleic acid, respectively. There were no differences in glucose metabolism among the cybrids. Osteoarthritis cybrids had lower acid-soluble metabolites, reflecting incomplete FA ß-oxidation but higher incorporation of oleic acid into triacylglycerol. Co-incubation with glucose and oleic acid showed that N but not OA cybrids increased their glucose metabolism. When treating with the mitochondrial inhibitor etomoxir, N cybrids still maintained higher glucose oxidation. Furthermore, OA cybrids had higher oxidative stress response. Combined, this indicated that N cybrids had higher metabolic flexibility than OA cybrids. Healthy donors maintained the glycolytic phenotype, whereas OA donors showed a preference towards oleic acid metabolism. Interestingly, the results indicated that cybrids from OA patients had mitochondrial impairments and reduced metabolic flexibility compared to N cybrids.