Objective In acute lymphoblastic leukemia (ALL), various clinical risk factors and genetic predispositions contribute to the development of bone complications during and after chemotherapy. In this study, we aimed to investigate whether vitamin D receptor (VDR) Fok1 and collagen protein Col1A1 Sp1-binding site gene polymorphisms, which are important in bone mineral and matrix formation, have effects on the development of bone abnormalities in childhood ALL survivors. Materials and methods Fifty children with ALL who were treated with the ALL Berlin-Frankfurt-Muenster-95 protocol between 1998 and 2008 and were followed for at least 7 years were enrolled. The control group consisted of 96 healthy children. VDR Fok1 and Col1A1 Sp1-binding site gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Bone mineral density (BMD) and markers of bone metabolism were all noted. All patients who presented with pain in the joints were examined for bone pathologies while on chemotherapy or during long-term follow-up. Results Low BMD (16%), osteoporosis (12%), and osteonecrosis (8%) were present in a total of 18 patients (36%). The frequency of osteonecrosis and total bone abnormalities was significantly higher in children aged ≥10 years (p=0.001). The risk of low BMD and osteonecrosis was higher in those with vitamin D deficiency. Only the Col1A1 Sp1-binding site gene polymorphism showed a significant association in ALL patients with osteonecrosis. Conclusion The development of therapy-induced bone mineral loss and osteonecrosis in children with ALL is frequent and the risk is especially higher in children aged ≥10 years and with vitamin D deficiency. The association between Col1A1 Sp1-binding site gene polymorphisms and osteonecrosis has to be assessed in a larger group of ALL survivors.

Investigation of the Relationship Between Fok1 and Col1A1 Gene Polymorphisms and Development of Treatment-Related Bone Complications in Children with Acute Lymphoblastic Leukemia

In recent years, genome wide association studies have revolutionized the understanding of the genetic architecture of complex disease, particularly in the context of disorders that present in old age, such as type 2 diabetes and cardiovascular disease. This new era is made all the more compelling by the fact that, through extensive validation efforts, there is now very strong consensus among human geneticists on what the key loci are that contribute to the pathogenesis of these traits. However, as these variants have been almost exclusively uncovered in an adult setting, there is the question of when these genetic variants start exerting their effects; indeed many may start setting up an individual's predisposition to a disease of old age very early on in life. To this end, we review what breakthroughs have been made in elucidating which of these genetic factors are operating in childhood and conversely what discoveries have actually been made in the pediatric setting that have then been found subsequently to increase one's risk of a late-onset disease. After all, it well known that complex traits like obesity, type 2 diabetes and inflammatory bowel disease are strongly determined by genetic factors, but the isolation of genes in these complex phenotypes in adults has been impeded by interaction with strong environmental factors. Distillation of the genetic component in these complex traits, which will at least partially have origins in childhood, should be easier to determine in a pediatric setting, where the relatively short period of a child's lifetime limits the impact of environmental exposure.

Developmental origins of genotype-phenotype correlations in chronic diseases of old age.

Background:Several studies have revealed a substantial increase in the incidence of fractures in children in the past few decades.Aim:To assess the strength of the association between suggested ris...

/pdf/vitamin-d-intake-calcium-intake-and-physical-activity-among-16esjk0si4.pdf

Vitamin D intake, calcium intake and physical activity among children with wrist and ankle injuries and the association with fracture risk:

Connective tissue is highly susceptible to imbalances induced by diabetes. Diabetes-related osteopenia, decreased bone strength etc. may be associated with altered metabolism of various collagens: Although it is assumed that alterations in collagen amino acids (AA) may strongly affect protein properties andphysiological functions, however, very limited evidences are present at the moment regarding AA composition of bone type I collagen and its relevance to abnormal availability of vitamins which are necessary for collagen synthesis in diabetes. We have tested whether nicotinamide (NAm) can influence type Icollagen formation and AA composition as well as vitamins availability in diabetes. After 4 weeks of STZ-induced diabetes (60 mg/ kg) male Wistar rats were injected for 2 weeks with/without NAm (200 mg/kg b. w). Acid extraction of type I collagen from the bones was performed with following stepwise salting out. The content of type I collagen after its acid extraction from the bones was estimated by the amounts of hydroxyproline. Amino acids were assayed by cation exchange chromatography Diabetes-associated changes in AA composition of type I collagen mainly affect those amino acids which are known to be involved in helix formation and cross-linking of the molecules. Diabetes was found to significantly reduce bone collagen contents of o-Pro, Gly, Ala, o-Lys and Pro, whereas Lys, His, Arg, Glu, Thr, Leu, Phe contents were elevated (P < 0.05). NAm treatment was able to partially normalise AA contents. In diabetes, blood serum and hepatic vitamin C and B3 contents were shown to be significantly lowered, whereas a-tocopherol was slightly increased compared with control (P < 0.05). Restoration of circulatory and liver vitamin C and B3 was observed. The data demonstrate the close relationship between the diabetes-associated decrease in type I collagen deposition, altered amino acids metabolism and impaired availability of vitamins, which are necessary for collagen synthesis. Thus, NAm might be a useful agent for treatment of bone failures related to diabetes.

/pdf/effect-of-nicotinamide-on-amino-acids-content-in-bone-md4srsvyio.pdf

Effect of nicotinamide on amino acids content in bone collagen depending on biological availability of vitamins in diabetic rats.

The reason for variations in peri-implant early crestal bone loss is unclear but may be due to genetic differences among individuals.The purpose of this nested case control study was to investigate the association of single-nucleotide polymorphisms of interleukin-1, interleukin-6, collagen type I alpha1, and osteocalcin genes to early crestal bone loss around submerged dental implants.Dental implants were placed in the mandibular posterior region (single edentulous space) of 135 participants selected according to predetermined selection criteria. Bone mineral density measurement by using dual energy X-ray absorptiometry, cone beam computed tomography scans at the baseline and after 6 months, and interleukin-1A-889 A/G (rs1800587), interleukin-1B-511 G/A (rs16944), interleukin-1B+3954 (rs1143634), interleukin-6-572 C/G (rs1800796), collagen type I alpha1 A/C (rs1800012), and osteocalcin C/T (rs1800247) genotyping were performed in all participants. Early crestal bone loss measured around dental implants was used to group participants into clinically significant bone loss (BL)>0.5 mm and clinically nonsignificant bone loss (NBL)≤0.5 mm. Early crestal bone loss was calculated as the mean of the difference of bone levels at the baseline and bone levels after 6 months as measured with cone beam computed tomography scans. The obtained data for basic characteristics, early crestal bone loss, and genotyping were tabulated and compared by using a statistical software program (α=.05).AA genotype and the A allele frequency of interleukin-1B-511 and GG genotype and the G allele frequency of interleukin-6-572 were significantly higher in BL than in NBL (P<.05). Multiple logistic analysis suggested that interleukin-1B-511 AA/GG+AG and interleukin-6-572 GG/CC+CG genotype expression were significantly associated with early crestal bone loss (AA/GG+AG; P=.014, GG/CC+CG; P=.047) around dental implants. Other risk factors were not significantly different (P>.05).Of the genes studied, individuals with interleukin-1B-511 AA (rs16944) or interleukin-6-572 GG (rs1800796) genotype had higher susceptibility to early crestal bone loss around dental implants. 

Association of interleukin-1, interleukin-6, collagen type I alpha 1, and osteocalcin gene polymorphisms with early crestal bone loss around submerged dental implants: A nested case control study

Collagen gene polymorphisms influence fracture risk and bone mass acquisition during childhood and adolescent growth.

Abstract Introduction/Background When investigating disease mechanisms, site-specific differences in immune cell phenotype and function have highlighted the need to analyse cellular and molecular mechanisms at the tissue site directly. In adults, the ability to obtain synovial tissue biopsies using ultrasound-guided techniques, combined with advanced tissue analytics, has revolutionised our understanding of the cellular ecosystem that operates within the joint and how it contributes to disease. However, a similar approach in paediatric disease is lacking. Description/Method Aims: 1) To describe the protocol for undertaking minimally invasive ultrasound-guided synovial tissue biopsies in children and young people with arthritis, for the purpose of research, alongside routine clinical care. 2) To investigate whether high-quality synovial tissue can be obtained that is suitable for downstream applications including single cell profiling technologies, histology and digital spatial profiling. Treatment-naïve children with a diagnosis of Juvenile Idiopathic Arthritis, who were being referred for a corticosteroid joint injection were recruited from two large UK Paediatric Rheumatology centres. We established a workflow pipeline for performing synovial tissue biopsies in child and young people with arthritis, using standardised procedures for biopsy and sample processing. Procedures were performed by experienced paediatric interventional radiologists with experience of joint biopsy for diagnostic purposes. Following a general anaesthetic, required as part of routine clinical care and the establishment of sterility, synovial fluid was aspirated. Needle-biopsies were undertaken from the same needle insertion site and subsequently corticosteroid was injected into the joint. Thickened synovium was graded via ultrasonography. Participating families completed questionnaires prior to and following synovial biopsy. Discussion/Results 11 participants were recruited to the study over a nine month period, with a median age of 7 years (range 1-16 years); 91% were female. Samples obtained included core synovial biopsies, paired synovial fluid and peripheral blood. Synovial tissue fragments were processed for histology by formalin fixation and cryopreserved for downstream applications, including RNA sequencing and cell culture. Quality control indices included histological analysis to ensure the biopsied material was characteristically synovium and to grade the severity of inflammation. No significant complications were reported; however, one child had a mild haemarthrosis controlled with cold saline wash out and cold compresses. Key learning points/Conclusion Obtaining biopsies of synovial tissue in children with Juvenile Idiopathic Arthritis for the purpose of research, alongside clinical care is feasible. Analysis of tissue direct from the site of inflammation with single-cell RNA sequencing in children is achievable.

/pdf/oa32-minimally-invasive-ultrasound-guided-tissue-biopsies-of-2z4u821w.pdf

OA32 Minimally invasive, ultrasound-guided tissue biopsies of synovial tissue in children with Juvenile Idiopathic Arthritis for research: a feasibility study

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Collagen gene polymorphisms influence fracture risk and bone mass acquisition during childhood and adolescent growth.

OA32 Minimally invasive, ultrasound-guided tissue biopsies of synovial tissue in children with Juvenile Idiopathic Arthritis for research: a feasibility study