Jose Riancho | Universidad de Cantabria (original) (raw)

Papers by Jose Riancho

$Research paper thumbnail of Osteogenic capacity of mesenchymal stem cells from patients with osteoporotic hip fractures in vivo$

Connective Tissue Research

Pharmaceutics

Mesenchymal stem cell (MSC) transplantation has emerged as a promising approach for bone regenera... more Mesenchymal stem cell (MSC) transplantation has emerged as a promising approach for bone regeneration. Importantly, the beneficial effects of MSCs can be improved by modulating the expression levels of specific genes to stimulate MSC osteogenic differentiation. We have previously shown that Smurf1 silencing by using Locked Nucleic Acid-Antisense Oligonucleotides, in combination with a scaffold that sustainably releases low doses of BMP-2, was able to increase the osteogenic potential of MSCs in the presence of BMP-2 doses significantly smaller than those currently used in the clinic. This would potentially allow an important reduction in this protein in MSs-based treatments, and thus of the side effects linked to its administration. We have further improved this system by specifically targeting the Wnt pathway modulator Sfrp1. This approach not only increases MSC bone regeneration efficiency, but is also able to induce osteogenic differentiation in osteoporotic human MSCs, bypassing...

Journal of Bone and Mineral Research

Phenotypic variation in skeletal traits and diseases is the product of genetic and environmental ... more Phenotypic variation in skeletal traits and diseases is the product of genetic and environmental factors. Epigenetic mechanisms include information-containing factors, other than DNA sequence, that cause stable changes in gene expression and are maintained during cell divisions. They represent a link between environmental influences, genome features, and the resulting phenotype. The main epigenetic factors are DNA methylation, posttranslational changes of histones, and higher-order chromatin structure. Sometimes non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are also included in the broad term of epigenetic factors. There is rapidly expanding experimental evidence for a role of epigenetic factors in the differentiation of bone cells and the pathogenesis of skeletal disorders, such as osteoporosis and osteoarthritis. However, different from genetic factors, epigenetic signatures are cell-and tissue-specific and can change with time. Thus, elucidating their role has particular difficulties, especially in human studies. Nevertheless, epigenomewide association studies are beginning to disclose some disease-specific patterns that help to understand skeletal cell biology and may lead to development of new epigenetic-based biomarkers, as well as new drug targets useful for treating diffuse and localized disorders. Here we provide an overview and update of recent advances on the role of epigenomics in bone and cartilage diseases.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2018

Parathyroid hormone (PTH) affects the skeleton by acting on osteocytes (Ots) in bone through yet ... more Parathyroid hormone (PTH) affects the skeleton by acting on osteocytes (Ots) in bone through yet unclear mechanisms. We report that matrix metalloproteinase 14 (MMP14) expression/activity are increased in bones from mice with genetic constitutive activation (ca) of the PTH receptor 1 (PTH1R) in Ots (caPTH1R) and in bones from mice exposed to elevated PTH levels but not in mice lacking [conditional knockout (cKO)] the PTH1R in Ots (cKOPTH1R). Furthermore, PTH upregulates MMP14 in human bone cultures and in Ot-enriched bones from floxed control mice but not from cKOPTH1R mice. MMP14 activity increases soluble receptor activator of NF-κΒ ligand production, which in turn, stimulates osteoclast differentiation and resorption. Pharmacologic inhibition of MMP14 activity reduced the high bone remodeling exhibited by caPTH1R mice or induced by chronic PTH elevation and decreased bone resorption but allowed full stimulation of bone formation induced by PTH injections, thereby potentiating bon...

Nature communications, Mar 8, 2018

Fundamental research and drug development for personalized medicine necessitates cell cultures fr... more Fundamental research and drug development for personalized medicine necessitates cell cultures from defined genetic backgrounds. However, providing sufficient numbers of authentic cells from individuals poses a challenge. Here, we present a new strategy for rapid cell expansion that overcomes current limitations. Using a small gene library, we expanded primary cells from different tissues, donors, and species. Cell-type-specific regimens that allow the reproducible creation of cell lines were identified. In depth characterization of a series of endothelial and hepatocytic cell lines confirmed phenotypic stability and functionality. Applying this technology enables rapid, efficient, and reliable production of unlimited numbers of personalized cells. As such, these cell systems support mechanistic studies, epidemiological research, and tailored drug development.

$Research paper thumbnail of Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density$

Annals of the rheumatic diseases, Jan 23, 2017

To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an i... more To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10(-9)) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 ...

Science & Justice

Biological samples from patients who have undergone allogeneic hematopoietic stem cell transplant... more Biological samples from patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) constitute a challenge for individual identification. In this study we analyzed the genetic profiles (by the amplification of 15 autosomic STRs) of HSCT patients found in different types of samples (blood, hair and urine) that may be the source of DNA in civil or criminal forensic cases. Our results show that while in hair follicles the donor component was not detected in any patient, thus being a reliable source of biological material for forensic identification, mixed chimerism was detected in urine samples from all patient, and no correlation was found between the time elapsed from the transplant and the percentage of chimerism. These results certainly have practical implications if the urine is being considered as a source of DNA for identification purposes in HSTC patients. Moreover, taking into consideration that chimerism was found not only in patients with leukocyturia (given the hematopoietic origin of leukocytes, this was expected), but also in those without observable leukocytes in the sediment, we conclude that an alternative source or sources of donor DNA must be implicated.

American journal of medical genetics. Part A, Jan 27, 2017

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mut... more Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a ...

Medicina clinica, Jan 29, 2017

Patients with Down syndrome have a number of risk factors that theoretically could predispose the... more Patients with Down syndrome have a number of risk factors that theoretically could predispose them to osteoporosis, such as early aging, development disorders, reduced physical activity, limited sun exposure, frequent comorbidities and use of drug therapies which could affect bone metabolism. In addition, the bone mass of these people may be affected by their anthropometric and body composition peculiarities. In general terms, studies in adults with Down syndrome reported that these people have lower areal bone mineral density (g/cm(2)) than the general population. However, most of them have not taken the smaller bone size of people with Down syndrome into account. In fact, when body mineral density is adjusted by bone size and we obtain volumetric body mineral density (g/cm(3)), the difference between both populations disappears. On the other hand, although people with Down syndrome have risk factor of hypovitaminosis D, the results of studies regarding 25(OH)D in this population a...

Journal of the Mechanical Behavior of Biomedical Materials, 2017

The influence of the orientation of rat bones on their mechanical response is analyzed in this re... more The influence of the orientation of rat bones on their mechanical response is analyzed in this research. 28 femora obtained from 14 Sprague-Dawley rats were subjected to three-point bending tests, comparing the anteroposterior and posteroanterior orientations. The results show that the whole-bone loading capacity of the femora tested in the posteroanterior orientation clearly exceeds that of the anteroposterior oriented bones. Likewise, the intrinsic (tissue-level) loading capacity of the bones tested in the posteroanterior orientation is manifestly higher than that of the bones tested in the opposite direction. The analysis carried out shows that applying beam theory for symmetric cross-sections leads to underestimating the stress state in the cross-section. In this sense, it is generally recommendable to use the non-symmetric beam theory in order to obtain the normal stresses during bending tests. The geometric, intrinsic and global changes resulting from the orientation of the bones was assessed, finding out that it is the variation in the intrinsic properties which explains the change measured in the whole-bone properties. The experimental scope was increased, including 8 additional femora on which a series of Vickers tests were carried out in the anterior and posterior regions of the cross-section. In all cases the hardness obtained in the anterior region is larger than in the posterior region. This result confirms that the mechanical properties of the bone tissue depend on its position in the cross-section and provides a reliable explanation to understand the response of the bones when subjected to bending tests. These results stress the importance of reporting the orientation of the bones in any scientific paper because, otherwise, it would be impossible to properly assess its impact and relevance.

International Journal of Legal Medicine, 2016

Several methods have been developed to determinate genetic profiles from a mixed samples and chim... more Several methods have been developed to determinate genetic profiles from a mixed samples and chimerism analysis in transplanted patients. The aim of this study was to explore the effectiveness of using the droplet digital PCR (ddPCR) for mixed chimerism detection (a mixture of genetic profiles resulting after allogeneic hematopoietic stem cell transplantation (HSCT)). We analyzed 25 DNA samples from patients who had undergone HSCT and compared the performance of ddPCR and two established methods for chimerism detection, based upon the Indel and STRs analysis, respectively. Additionally, eight artificial mixture DNA samples were created to evaluate the sensibility of ddPCR. Our results show that the chimerism percentages estimated by the analysis of a single Indel using ddPCR were very similar to those calculated by the amplification of 15 STRs (r (2) = 0.970) and with the results obtained by the amplification of 38 Indels (r (2) = 0.975). Moreover, the amplification of a single Indel by ddPCR was sensitive enough to detect a minor DNA contributor comprising down to 0.5 % of the sample. We conclude that ddPCR can be a powerful tool for the determination of a genetic profile of forensic mixtures and clinical chimerism analysis when traditional techniques are not sensitive enough.

Corros Sci, 2011

El tejido óseo se renueva constantemente por la acción coordinada de osteoclastos y osteoblastos.... more El tejido óseo se renueva constantemente por la acción coordinada de osteoclastos y osteoblastos. Los osteocitos desempeñan un papel destacado en el inicio del remodelado en un lugar dado del esqueleto. Estos y otras células de estirpe osteoblástica producen diversos mediadores que modulan la diferenciación de los precursores osteoclásticos, paso inicial imprescindible para que comience la resorción. Entre ellos, son especialmente importantes el M-CSF y el RANKL.Bone tissue is constantly renewed by the coordinated action of osteoclasts and osteoblasts. Osteocytes have a prominent role in the onset of bone remodeling at selected sites of the skeleton. These and other osteoblastic cells produce a variety of mediators that modulate the differentiation of osteoclast precursors, a critical step for bone resorption to occur. Among them, M-CSF and RANKL are especially important.

Medicina Clinica, 2009

Alcoholizació n: una opció n para el tratamiento del hiperparatiroidismo Alcoholization: an optio... more Alcoholizació n: una opció n para el tratamiento del hiperparatiroidismo Alcoholization: an option for the treatment of hyperparathyroidism Sr. Editor:

Medicina Clinica, Jul 4, 1998

... Fundamento: La tromboembolia pulmonar (TEP) continúa siendo de diagnóstico difícil. Las técni... more ... Fundamento: La tromboembolia pulmonar (TEP) continúa siendo de diagnóstico difícil. Las técnicas de imagen disponibles tienen un rendimiento limitado, por lo que sus resultados deben interpretarse teniendo en cuenta la probabilidad pretest de TEP, que se estima, de ...

Journal of Bone and Mineral Research the Official Journal of the American Society For Bone and Mineral Research, Sep 30, 2009

BMD has a strong heritable component. Estrogen activity depends on the aromatization of androgeni... more BMD has a strong heritable component. Estrogen activity depends on the aromatization of androgenic precursors in nongonadal tissues both in postmenopausal women and men. Therefore, aromatase is an appealing candidate gene to explain, in part, the genetic component of BMD. In fact, an association between aromatase polymorphisms and BMD has been previously reported in some relatively small groups. In this study, we explored the relationship between several SNPs in the aromatase region and hip BMD in 1163 postmenopausal women. We found significant differences across genotypes, particularly in older women. The BMD differences between homozygous women with opposing genotypes were 4.2% in the whole group and 7.3% in women >67 yr of age. Body weight was significantly associated with BMD also, but there was no evidence for a statistically significant interaction between body weight and aromatase polymorphisms. Electrophoretic mobility shift assays suggested the binding of the CEBPß transcription factor to the C/G rs1062033 locus, located ;12 kb upstream of the translation start site. Experiments of transient transfection of osteoblastic cells with luciferase reporters showed differences in the transcriptional activity of alleles C and G at this locus, with different responses to the co-transfection of a CEBPß expression vector. Furthermore, evidence for differential allelic expression was found in bone tissue samples. In conclusion, polymorphisms in a 12-kb region of the aromatase gene are associated with BMD in postmenopausal women, particularly during the late postmenopausal period. In vitro functional studies point to rs1062033 as a true regulatory polymorphism.

Journal of translational medicine, 2016

Age-associated changes in genomic DNA methylation have been primarily attributed to 5-methylcytos... more Age-associated changes in genomic DNA methylation have been primarily attributed to 5-methylcytosine (5mC). However, the recent discovery of 5-hydroxymethylcytosine (5hmC) suggests that this epigenetic mark might also play a role in the process. Here, we analyzed the genome-wide profile of 5hmc in mesenchymal stem cells (MSCs) obtained from bone-marrow donors, aged 2-89 years. We identified 10,685 frequently hydroxymethylated CpG sites in MSCs that were, as in other cell types, significantly associated with low density CpG regions, introns, the histone posttranslational modification H3k4me1 and enhancers. Study of the age-associated changes to 5hmC identified 785 hyper- and 846 hypo-hydroxymethylated CpG sites in the MSCs obtained from older individuals. DNA hyper-hydroxymethylation in the advanced-age group was associated with loss of 5mC, which suggests that, at specific CpG sites, this epigenetic modification might play a role in DNA methylation changes during lifetime. Since bon...

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Bone tissue is constantly renewed by the coordinated action of osteoclasts and osteoblasts. Osteo... more Bone tissue is constantly renewed by the coordinated action of osteoclasts and osteoblasts. Osteocytes have a prominent role in the onset of bone remodeling at selected sites of the skeleton. These and other osteoblastic cells produce a variety of mediators that modulate the differentiation of osteoclast precursors, a critical step for bone resorption to occur. Among them, M-CSF and RANKL are especially important.

Current Genomics, 2012

Bone is a specialized connective tissue with a calcified extracellular matrix in which cells are ... more Bone is a specialized connective tissue with a calcified extracellular matrix in which cells are embedded. Besides providing the internal support of the body and protection for vital organs, bone also has several important metabolic functions, especially in mineral homeostasis. Far from being a passive tissue, it is continuously being resorbed and formed again throughout life, by a process known as bone remodeling.Bone development and remodeling are influenced by many factors, some of which may be modifiable in the early steps of life. Several studies have shown that environmental factors in uterus and in infancy may modify the skeletal growth pattern, influencing the risk of bone disease in later life. On the other hand, bone remodeling is a highly orchestrated multicellular process that requires the sequential and balanced events of osteoclast-mediated bone resorption and osteoblast-mediated bone formation. These processes are accompanied by specific gene expression patterns which are responsible for the differentiation of the mesenchymal and hematopoietic precursors of osteoblasts and osteoclasts, respectively, and the activity of differentiated bone cells. This review summarizes the current understanding of how epigenetic mechanisms influence these processes and their possible role in common skeletal diseases.