ABSTRACT: Studies in Aotearoa New Zealand found higher bone mineral density and lower rate of hip fracture in people of Polynesian ancestry compared to Europeans. We hypothesised that differences in osteoblast gene expression contribute to the differences in bone properties between the two groups, and aimed to identify mechanisms that underlie the bone phenotype.
Project description:Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans, primarily performed to evaluate bone density and osteoporosis risk. Here, we report on a genome-wide association (GWA) study of DXA bone area of the hip and spine (N ≥ 28,954). We found associations of common variants at eleven loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). We also examined association of these markers with osteoarthritis and fractures in European samples (Ncases = 3,293 – 27,321). The strongest DXA area association is with a variant in the microRNA MIR196A2 gene at the HOXC locus that associates with reduced lumbar spine area (rs11614913[T], P = 2.3 × 10-42, β = −0.090) and confers risk of hip fractures (P = 1.0 × 10-8, OR = 1.11). We demonstrate that the hip fracture risk allele [T] is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density. Eight DXA area loci associate with osteoarthritis, including rs143384 in the 5’ UTR of the GDF5 gene and a missense variant in the COL11A1 gene (rs3753841[G], NP_001177638.1:p.Pro1284Leu). We also report a complex relationship between the variants associated with DXA area measures and height and bone mineral density (BMD).
Project description:Comparison of circulating monocytes from pre- and postmanopausal females with low or high bone mineral density (BMD). Circulating monocytes are progenitors of osteoclasts, and produce factors important to bone metabolism. Results provide insight into the role of monocytes in osteoporosis. We identify osteoporosis genes by microarray analyses of monocytes in high vs. low hip BMD (bone mineral density) subjects. Microarray analyses of monocytes were performed using Affymetrix HG-133A arrays in 80 Caucasian females, including 40 high (20 pre- and 20 postmanopausal) and 40 low hip BMD (20 pre- and 20 postmanopausal) subjects
Project description:Subchondral bone samples from six patients who underwent primary total hip arthroplasty (three ONFH patients and three patients in control group with femoral neck fracture) were obtained.
Project description:Osteoporosis and bone fragility fracture are multifactorial pathologies whose genetic component is still poorly characterized. The present experiment aims to identify genes differentially expressed in the bone-forming cell; the osteoblast. To do this, we obtain primary osteoblasts from bone explants of women undergoing hip replacement to later obtain RNA. The cases are women with a fragility bone fracture of the hip. The controls are women with severe osteoarthritis.Microarray analysis yielded 2542 differentially expressed transcripts belonging to 1798 annotated genes, of which 45.6% (819) were overexpressed, and 54.4% (979) underexpressed (fold-change between -7.45 and 4.0). Among the most represented pathways indicated by transcriptome analysis were chondrocyte development, positive regulation of bone mineralization, BMP signaling pathway, skeletal system development and Wnt signaling pathway. Then, we selected SNPs in genes related to epigenetic mechanisms to study their association with bone mass in a cohort of 1028 Spanish women. We used microarrays to compare the overall gene expression between primary osteoblasts from women with fragility fracture with that of control women undergoing hip replacement due to severe osteoatritis.
Project description:Comparison of circulating monocytes from pre- and postmenopausal females with low or high bone mineral density (BMD). Circulating monocytes are progenitors of osteoclasts, and produce factors important to bone metabolism. Results provide insight into the role of monocytes in osteoporosis. We identify osteoporosis genes by microarray analyses of monocytes in high vs. low hip BMD (bone mineral density) subjects.
Project description:Comparison of circulating monocytes from pre- and postmanopausal females with low or high bone mineral density (BMD). Circulating monocytes are progenitors of osteoclasts, and produce factors important to bone metabolism. Results provide insight into the role of monocytes in osteoporosis. We identify osteoporosis genes by microarray analyses of monocytes in high vs. low hip BMD (bone mineral density) subjects.
Project description:In the present study we analyzed the effect of primary osteoporosis and advanced donor age on the transcriptome of human mesenchymal stem cells (hMSC; alternatively named mesenchymal stromal cells) from bone marrow. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Control cells were obtained from bone marrow of femoral heads of middle-aged, non-osteoporotic donors after total hip arthroplasty. Cells were isolated from human bone marrow according to the previously described protocol (Noth et al., 2002, J Orthop Res, 20/5, 1060-1069) under agreement of the local Ethics Committee of the University of Würzburg. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Additional criteria for confirming primary osteoporosis in these donors were vertebrae fractures and advanced age. Bone marrow of middle-aged, non-osteoporotic donors was obtained of femoral heads after total hip arthroplasty due to osteoarthritis and/or hip dysplasia. RNA samples were taken from passage 1 or passage 2.
Project description:In the present study we analyzed the effect of primary osteoporosis on the transcriptome of human mesenchymal stem cells (hMSC; alternatively named mesenchymal stromal cells) from human bone marrow. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Bone marrow of age-matched, non-osteoporotic donors was obtained of femoral heads after total hip arthroplasty. Cells were isolated from human bone marrow according to the previously described protocol (Noth et al., 2002, J Orthop Res, 20/5, 1060-1069) under agreement of the local Ethics Committee of the University of Würzburg. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Additional criteria for confirming primary osteoporosis in these donors were vertebrae fractures and advanced age. Bone marrow of age-matched, non-osteoporotic donors was obtained of femoral heads after total hip arthroplasty due to osteoarthritis and/or hip dysplasia. RNA samples were taken from passage 1 or passage 2.
Project description:Comparison of circulating monocytes from pre- and postmenopausal females with low or high bone mineral density (BMD). Circulating monocytes are progenitors of osteoclasts, and produce factors important to bone metabolism. Results provide insight into the role of monocytes in osteoporosis. We identify osteoporosis genes by microarray analyses of monocytes in high vs. low hip BMD (bone mineral density) subjects. Microarray analyses of monocytes were performed using Affymetrix 1.0 ST arrays in 73 Caucasian females (age: 47-56) with extremely high (mean ZBMD =1.38, n=42, 16 pre- and 26 postmenopausal subjects) or low hip BMD (mean ZBMD=-1.05, n=31, 15 pre- and 16 postmenopausal subjects). Differential gene expression analysis in high vs. low BMD subjects was conducted in the total cohort as well as pre- and post-menopausal subjects.
Project description:<p>Osteoporotic fractures are largely due to an increased propensity to fall with aging and a reduction in bone strength.
Although skeletal architecture contributes to fracture risk, bone mineral density (BMD) is the most important determinant of bone
strength and fracture risk. Between 60 and 80% of the variance of BMD of adult Caucasian women is due to heritable factors.
Final BMD is a function of peak bone mass attained during young adulthood and the subsequent rate of bone loss, which occurs
as a result of both post-menopausal estrogen loss and aging. The evidence for a genetic contribution to rate of loss in BMD is substantially
weaker than that for peak BMD. Therefore, we have focused our sample collection on the recruitment of premenopausal women, in whom we have
sought to identify the genes influencing peak BMD at the spine and hip, the two major skeletal sites of osteoporotic fracture.</p>
<p>The primary goal of this study is to identify genes that affect peak BMD in premenopausal women. Identification of these genes may:
1) lead to molecular tests that predict risk of osteoporosis and allow institution of early preventive measures; 2) provide insight
into basic bone cell biology and other factors that affect peak BMD; and 3) provide molecular targets for therapeutic agents to increase BMD.</p>