Mitochondrial DNA in Osteoarthritis Disease

[Abstract] Osteoarthritis (OA) is the most prevalent chronic joint disease, and we actually know that the activation of maladaptive responses to injury, including pro-inflammatory pathways, leads to the loss of normal joint function characterized by cartilage degradation, bone remodeling, osteophyte formation, and joint inflammation [1]. Recent insights into the epidemiology and impact of OA on patients have clearly established that OA is a severe disease of the whole joint as an organ, with large unmet medical needs. OA has a complex etiology that comprises the combination of multiple factors, including gender, age, occupation, trauma, body mass index, and genetics. Approximately, between 30 and 65% of the risk of OA is genetically determined [2] with evidence accumulated from different genome-wide association studies (GWAS) [3]. Most of these studies focused on nuclear genetic variants; however, over the last decade, evidence has accumulated for an association between specific mitochondrial DNA (mtDNA) genetic variants, called haplogroups, and different OA-related features, including prevalence, progression, and incidence [4].Instituto de Salud Carlos III; CIBERCB06/01/0040Instituto de Salud Carlos III; RETIC-RIER-RD16/0012/0002Instituto de Salud Carlos III; PRB2-ISCIII-PT17/0019/0014Instituto de Salud Carlos III; PI14/01254Instituto de Salud Carlos III; PI16/02124Instituto de Salud Carlos III; PI17/0021

Mitochondria and Mitophagy: Biosensors for Cartilage Degradation and Osteoarthritis

Editoria

Análisis de marcadores RAPDs en el género Mytilus

[Resumen] Se realiza un análisis poblacional, mediante marcadores RAPDs (Random Amplified Polymorphic DNA), de la estructura genética de 12 poblaciones de mejillón pertenecientes al género Mytilus, procedentes de diferentes lugares geográficos. Este trabajo constituye el primer ensayo, aplicando este tipo de marcador molecular, en un número tan elevado de poblaciones de mejillón. Los resultados obtenidos reflejan, en base al análisis de 32 loci polimórficos, la existencia de una elevada variabilidad genética, tanto intrapoblacional como intraespecífica y, como consecuencia, revelan el establecimiento de una estructura genética definida. Por otra parte, se ha detectado la existencia de una estructura panmíctica a nivel de las 3 localidades gallegas de M.galloprovincialis, así como un flujo genético restringido entre las poblaciones europeas de mejillón, probablemente relacionado con la existencia de barreras genéticas a lo largo de la costa Oeste de Europa. El conjunto de análisis realizados, que incluyen componentes princiaples, análisis de la varianza molecular, estimadores de distancia, índices de fijación y diferentes topologías, también reveló la posible presencia de individuos híbridos M.edulis-M.trossulus en la población de Isle of Man, así como la posible influencia humana en el establecimiento del flujo genético. El análisis de las especies japonesas que cohabitan la Bahía de Otsuchi (M.galloprovincialis y M.coruscus) reveló una mayor proximidad de éstas a M.californianus que a culaquier otra forma de mejillón. Asimismo, se han desarrollado marcadores, diagnóstico que permiten identificar inequívocamente determinadas especies de mejillón de interés comercial con el fin de evitar posibles fraudes, lo cual, desde el punto de vista de su aplicación industrial, resulta de un elevado interés. En este sentido se ha desarrollado un marcador que permite identificar stocks de poblaciones de M.galloprovinci

Is osteoarthritis a mitochondrial disease?: what is the evidence

Final peer-reviewed manuscript[Abstract] 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.Instituto de Salud Carlos III; PI17/00210Instituto de Salud Carlos III; PI20/00614Instituto de Salud Carlos III; PI19/01206Instituto de Salud Carlos III; RETIC-RIER-RD16/0012/000

What did we learn from 'omics' studies in osteoarthritis

Review article[Abstract] Purpose of review: 'Omics' technologies developed for the massive analysis of the major biologically relevant molecules (genes, proteins, metabolites) have been applied to the study of osteoarthritis (OA) for more than a decade. Recent findings: 'Omics' studies have undoubtedly contributed to increase the knowledge on pathogenic processes related with OA and have provided hundreds to thousands of molecules that might have a putative biomarker utility for this disease. Summary: This review describes the most recent 'omics' studies in OA research, their conclusions, and discuss those remaining challenges. Still many validation studies must be performed in large and well-characterized cohorts for the translation of the findings from 'omics' strategies to clinical applications. The development of tools for the intelligent integration of 'omics' data with clinical and imaging information is also mandatory to take full profit of the work that has been already performed.Instituto de Salud Carlos III; PI14/01707Instituto de Salud Carlos III; PI14/01254Instituto de Salud Carlos III; PI16/02124Instituto de Salud Carlos III; CIBERCB06/ 01/0040Instituto de Salud Carlos III; RETIC-RIER-RD12/0009/0018Instituto de Salud Carlos III; PT13/000

Gene Polymorphisms and Pharmacogenetics in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic, chronic and inflammatory disease of unknown etiology with genetic predisposition. The advent of new biological agents, as well as the more traditional disease-modifying antirheumatic drugs, has resulted in highly efficient therapies for reducing the symptoms and signs of RA; however, not all patients show the same level of response in disease progression to these therapies. These variations suggest that RA patients may have different genetic regulatory mechanisms. The extensive polymorphisms revealed in non-coding gene-regulatory regions in the immune system, as well as genetic variations in drug-metabolizing enzymes, suggest that this type of variation is of functional and evolutionary importance and may provide clues for developing new therapeutic strategies. Pharmacogenetics is a rapidly advancing area of research that holds the promise that therapies will soon be tailored to an individual patient’s genetic profile

Leukocyte telomere length in patients with radiographic knee osteoarthritis

Brief communication[Abstract] Relative mean telomere sequence amount was determined by quantitative PCR (qPCR) of peripheral blood leukocyte (PBL) samples obtained at recruitment (n = 310) from individuals from the Osteoarthritis (OA) Initiative consortium. Knees were radiologically evaluated according to the Kellgren–Lawrence (KL) score, ranging from 0 to 4, considering a KL grade ≥ 2 as radiographic evidence of OA (n = 124). Telomere size decreased as baseline KL score increased, being significantly shorter in subjects with KL ≥2 (Mann–Whitney U‐test, P < 0.0001). PBL telomere size was also associated with age, hypertension, body mass index (BMI) and waist circumference. Nevertheless, logistic regression analysis showed that PBL telomere size was a consistent risk factor for concurrent knee OA, independent of these health parameters. Shorter PBL telomeres may indicate a premature aging status which enhances chondrocyte senescence and degenerative joint disease.Instituto de Salud Carlos III; PI17/01987Instituto de Salud Carlos III; PI16/0212

Mitochondrial genetics and epigenetics in osteoarthritis

Review[Abstract] During recent years, the significant influence of mitochondria on osteoarthritis (OA), the most common joint disease, has been consistently demonstrated. Not only mitochondrial dysfunction but also mitochondrial genetic polymorphisms, specifically the mitochondrial DNA haplogroups, have been shown to have an important influence on different OA-related features, including the prevalence, severity, incidence, and progression of the disease. This influence could probably be mediated by the role of mitochondria in the regulation of different processes involved in the pathogenesis of OA, such as energy production, the generation of reactive oxygen and nitrogen species, apoptosis, and inflammation. The regulation of these processes is at least partially controlled by the bi-directional communication between the nucleus and mitochondria, which permits the regulation of adaptation to a wide range of stressors and the maintenance of cellular homeostasis. This bi-directional communication consists of an “anterograde regulation” by which the nucleus regulates mitochondrial biogenesis and activity and a “retrograde regulation” by which both mitochondria and mitochondrial genetic variation exert a regulatory signaling control over the nuclear epigenome, which leads to the modulation of nuclear genes. Throughout this mini review, we will describe the evidence that demonstrates the profound influence of the mitochondrial genetic background in the pathogenesis of OA, as well as its influence on the nuclear DNA methylome of the only cell type present in the articular cartilage, the chondrocyte. This evidence leads to serious consideration of the mitochondrion as an important therapeutic target in OA.Instituto de Salud Carlos III; CIBERCB06/01/0040Instituto de Salud Carlos III; RETIC-RIER-RD16/0012/0002Instituto de Salud Carlos III; PRB2-ISCIII-PT17/0019/0014Instituto de Salud Carlos III; PI14/01254Instituto de Salud Carlos III; PI16/02124Instituto de Salud Carlos III; PI17/00210Instituto de Salud Carlos III; (CPII17/00026

Genetic biomarkers in osteoarthritis: a quick overview

[Abstract] 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.Instituto de Salud Carlos III; PI17/00210Instituto de Salud Carlos III; PI16/02124Instituto de Salud Carlos III; PI20/00614Instituto de salud Carlos III; RETIC-RIER-RD16/0012/0002Instituto de Salud Carlos III; PRB3-ISCIII-PT17/0019/0014Xunta de Galicia; IN607A2017/1

DNA content, karyotypes, and chromosomal location of 18S-5.8S-28S ribosomal loci in some species of bivalve molluscs from the Pacific Canadian coast

[Abstract]: The DNA content of 10 species of bivalve molluscs from British Columbia coast was determined by image analysis, and the karyotypes of the horse clam “Tressus capax”, the bent-nose macoma “Macoma nasuta”, and the nuttall's mahogany clam “Nuttallia nuttallii” are described here for the first time. We also have analyzed the location of rDNA loci using a 28S-5.8S-18S probe in four of these species: “Mytilus californianus”, “M. trossulus”, “Macoma nasuta” and “N. nuttallii”. Results obtained report new data about cytogenetic characteristics of bivalve molluscs.Xunta de Galicia; 10303B93Xunta de Galicia; 10306B95Natural Sciences and Engineering Research Council of Canada (NSERC); OGP 004639