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Nilsson, Olle
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Publications (10 of 45) Show all publications
Laxman, N., Mallmin, H., Nilsson, O. & Kindmark, A. (2017). miR-203 and miR-320 regulate Bone Morphogenetic Protein-2-induced osteoblast differentiation by targeting Distal-less Homeobox 5 (Dlx5). Genes, 8(1), Article ID E4.
Open this publication in new window or tab >>miR-203 and miR-320 regulate Bone Morphogenetic Protein-2-induced osteoblast differentiation by targeting Distal-less Homeobox 5 (Dlx5)
2017 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 8, no 1, article id E4Article in journal (Refereed) Published
Abstract [en]

MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17–24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-264442 (URN)10.3390/genes8010004 (DOI)000399057100004 ()
Funder
Swedish Research Council, 2009-2852
Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2018-09-04Bibliographically approved
Laxman, N., Rubin, C.-J., Mallmin, H., Nilsson, O., Tellgren-Roth, C. & Kindmark, A. (2016). Second generation sequencing of microRNA in Human Bone Cells treated with Parathyroid Hormone or Dexamethasone. Bone, 84, 181-188
Open this publication in new window or tab >>Second generation sequencing of microRNA in Human Bone Cells treated with Parathyroid Hormone or Dexamethasone
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2016 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 84, p. 181-188Article in journal (Refereed) Published
Abstract [en]

We investigated the impact of treatment with parathyroid hormone (PTH) and dexamethasone (DEX) for 2 and 24 h by RNA sequencing of miRNAs in primary human bone (HOB) cells. A total of 207 million reads were obtained, and normalized absolute expression retrieved for 373 most abundant miRNAs. In naive control cells, 7 miRNAs were differentially expressed (FDR < 0.05) between the two time points. Ten miRNAs exhibited differential expression (FDR < 0.05) across two time points and treatments after adjusting for expression in controls and were selected for downstream analyses. Results show significant effects on miRNA expression when comparing PTH with DEX at 2 h with even more pronounced effects at 24 h. Interestingly, several miRNAs exhibiting differences in expression are predicted to target genes involved in bone metabolism e.g. miR-30c2, miR-203 and miR-205 targeting RUNX2, and miR-320 targeting beta-catenin (CTNNB1) mRNA expression. CTNNB1 and RUNX2 levels were decreased after DEX treatment and increased after PTH treatment. Our analysis also identified 2 putative novel miRNAs in PTH and DEX treated cells at 24 h. RNA sequencing showed that PTH and DEX treatment affect miRNA expression in HOB cells and that regulated miRNAs in turn are correlated with expression levels of key genes involved in bone metabolism.

Keywords
miRNA; osteoblasts; RNA sequencing; differential expression
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-264440 (URN)10.1016/j.bone.2015.12.053 (DOI)000370914600021 ()26748295 (PubMedID)
Funder
Swedish Research Council, 2009-2852
Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2017-12-01Bibliographically approved
Laxman, N., Rubin, C.-J., Mallmin, H., Nilsson, O., Pastinen, T., Grundberg, E. & Kindmark, A. (2015). Global miRNA expression and correlation with mRNA levels in primary human bone cells. RNA: A publication of the RNA Society, 21(8), 1433-1443
Open this publication in new window or tab >>Global miRNA expression and correlation with mRNA levels in primary human bone cells
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2015 (English)In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 21, no 8, p. 1433-1443Article in journal (Refereed) Published
Abstract [en]

MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, alpha 1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.

Keywords
miRNA, mRNA, osteoblasts, interindividual variation, differential expression
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-260282 (URN)10.1261/rna.049148.114 (DOI)000358016000005 ()26078267 (PubMedID)
Funder
Swedish Research Council
Available from: 2015-08-21 Created: 2015-08-18 Last updated: 2017-12-04Bibliographically approved
Hailer, Y. D., Haag, A. C. & Nilsson, O. (2014). Legg-Calvé-Perthes Disease: Quality of Life, Physical Activity, and Behavior Pattern. Journal of Pediatric Orthopaedics, 34(5), 514-521
Open this publication in new window or tab >>Legg-Calvé-Perthes Disease: Quality of Life, Physical Activity, and Behavior Pattern
2014 (English)In: Journal of Pediatric Orthopaedics, ISSN 0271-6798, E-ISSN 1539-2570, Vol. 34, no 5, p. 514-521Article in journal (Refereed) Published
Abstract [en]

Background: Legg-Calve-Perthes disease (LCPD) is a disease in children leading to deformation of the femoral head and can be a promoter for early dysfunction of the hip and early osteoarthritis of the hip. The study of health-related quality of life, physical activity, and behavior patterns in patients with LCPD can reveal its consequences later in life and also contribute to a better understanding of the etiology of the disease.

Patients and Methods: We identified 145 patients with LCPD diagnosed and treated at Uppsala University Hospital between 1978 and 1995. A total of 116 patients answered questionnaires regarding health-related quality of life (EQ-5D-3L), physical activity [International Physical Activity Questionnaire (IPAQ)], and hyperactive/inattentive behavior pattern [ADHD self-reporting symptom checklist (ASRS v1.1)] by interview. Patients were asked to report on fractures or soft-tissue injuries that required medical care. Medical charts were reviewed to determine age at onset of LCPD and treatment received.

Results: Patients with LCPD had significantly lower EQ-5D-3L and EQ VAS scores than the Swedish general population in all age groups. A total of 28% of our patient group had ASRS scores indicating they are likely or highly likely to have an ADHD diagnosis. A lower EQ-5D-3L score was significantly correlated with a higher total ASRS v1.1 score (=-0.309**). Over 90% of our patient group was physically active on a moderate or high level, despite 52% reporting either some or severe problems with pain according to the EQ-5D-3L questionnaire. Patients with high ASRS v1.1 scores (>16) had a significantly higher incidence of soft-tissue injuries than those with lower ASRS v1.1 scores.

Conclusion: The consequence of LCPD in adulthood was expressed in a lower quality of life compared with the Swedish general population. Despite this, the patients in our study reported a higher level of physical activity than the general population. A tendency toward hyperactive behavior pattern and high physical activity level may be present even in childhood and could contribute to the etiology of LCPD.

Level of Evidence: A retrospective study, level II.

Keywords
LCPD, quality of life, physical activity, ADHD, injury
National Category
Orthopaedics
Research subject
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-219157 (URN)10.1097/BPO.0000000000000157 (DOI)000337745800009 ()
Available from: 2014-03-09 Created: 2014-02-24 Last updated: 2018-01-11Bibliographically approved
Ullmark, G., Nilsson, O., Maripuu, E. & Sörensen, J. (2013). Analysis of bone mineralization on uncemented femoral stems by [18F]-fluoride-PET. Acta Orthopaedica, 84(2), 138-144
Open this publication in new window or tab >>Analysis of bone mineralization on uncemented femoral stems by [18F]-fluoride-PET
2013 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 84, no 2, p. 138-144Article in journal (Refereed) Published
Abstract [en]

Purpose We present the first study using fluoride-positron emission CT (F-PET/CT) to analyze mineralization of bone in the femur adjacent to uncemented stems following total hip arthroplasty (THA). We studied patients who were operated bilaterally for osteoarthritis with 2 different stems during the same surgical session. Patients and methods THA was performed bilaterally during the same surgical session in 8 patients with bilateral osteoarthritis of the hip. An SL-PLUS stem was inserted in one hip and a Beta Cone stem was inserted in the contralateral hip, with randomization of side and sequence. A second group of 12 individuals with a normal healthy hip was used as reference for normal bone metabolism. Clinical and radiographic evaluation was performed preoperatively, postoperatively, and at 2 years. We used [18F]-fluoride-PET/CT to analyze bone mineralization adjacent to the stems 1 week, 4 months, and 12 months after surgery. We modified the Polar Map system to fit the upper femur for analysis and presentation of the PET results from 12 regions of interest adjacent to the whole stem. Results The clinical results were good at 2 years. By radiography, all stems were stable. At PET analyses 1 week after surgery, the activity was higher for the SL-PLUS group than for the BetaCone group. The activity was statistically significantly higher for both stems than the reference values at 4 months, and was most pronounced in the upper femur. At one year, the activity had declined more for the BC group than for the SL group. Interpretation The bone mineralization activity varied between different regions for the same stem and between different time periods for each group. F-PET/CT is a novel and valuable tool for analysis of bone mineralization patterns around uncemented femoral stems in detail. The combination of PET/CT analysis and the modified Polar Map system may provide a useful tool for future studies of metabolic bone responses to prosthetic implants.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-200359 (URN)10.3109/17453674.2013.786632 (DOI)000317661500004 ()
Available from: 2013-05-28 Created: 2013-05-27 Last updated: 2017-12-06Bibliographically approved
Sisask, G., Marsell, R., Sundgren-Andersson, A., Larsson, S., Nilsson, O., Ljunggren, Ö. & Jonsson, K. B. (2013). Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation. Bone, 54(1), 126-132
Open this publication in new window or tab >>Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation
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2013 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 54, no 1, p. 126-132Article in journal (Refereed) Published
Abstract [en]

Fracture healing is a complex interplay between endochondral and intramembranous bone formation processes. The canonical Wnt/β-catenin pathway enhances new bone formation and may play a role in fracture healing. Glycogen synthase kinase 3β (GSK3β) is a key regulator of β-catenin degradation. In this study, we investigate the effects of AZD2858, an orally bioactive GSK3 inhibitor, on fracture healing. Femoral fractures were produced in rats after the insertion of a femoral nail. The rats were treated with oral administration of AZD2858 at a dose of 30μmol/kg (20mg/kg) daily for up to 3weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3weeks, histological analysis was performed, and at the 2 and 3week time points, we performed peripheral quantitative computed tomography (pQCT), X-rays, and four-point bending tests. Peripheral QCT showed an increase in both mineral density (of 28% at 2weeks and 38% at 3weeks) and mineral content (of 81% at 2weeks and 93% at 3weeks) in the calluses from AZD2858 treated animals as compared to vehicle treated animals. Histological analysis demonstrated that rats treated with GSK3 inhibitor healed their fractures rapidly, but without the pre-formation of cartilage tissue. Furthermore, four-point bending tests of fractured femora from animals treated for 2 and 3weeks showed an increase in strength in treated animals compared to their vehicle-treated controls. In conclusion, AZD2858, a potent GSK3 inhibitor, has a substantial impact on fracture healing. The fractures healed with a bony callus without an obvious endochondral component, suggesting that AZD2858 drives mesenchymal cells into the osteoblastic pathway. This leads to direct bone repair in an unstable fracture milieu.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-193321 (URN)10.1016/j.bone.2013.01.019 (DOI)000316839800017 ()23337038 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2017-12-06Bibliographically approved
Ullmark, G., Sörensen, J. & Nilsson, O. (2012). Analysis of bone formation on porous and calcium phosphate-coated acetabular cups: a randomised clinical [18F]fluoride PET study. HIP International, 22(2), 172-178
Open this publication in new window or tab >>Analysis of bone formation on porous and calcium phosphate-coated acetabular cups: a randomised clinical [18F]fluoride PET study
2012 (English)In: HIP International, ISSN 1120-7000, E-ISSN 1724-6067, Vol. 22, no 2, p. 172-178Article in journal (Refereed) Published
Abstract [en]

We present a study using Fluoride-Positron Emission Tomography (F-PET/CT) to analyse new bone formation in periacetabular bone adjacent to press fit cups following THA. In 16 THA (8 patients) with bilateral hip osteoarthritis simultaneous bilateral total hip arthroplasty (THA) was performed, employing electrochemically applied calcium phosphate coated (HA) cups or porous-coated (PC) cups allocated at random to compare the two sides. A reference group of 13 individuals with a normal healthy hip was used to determine 'normal' bone metabolism. [18F]fluoride -PET/CT was used to analyze bone formation adjacent to the cups 1 week, 4 months and 12 months after surgery. Clinical and radiographic evaluation was performed preoperatively, postoperatively and at 2 years. Bone forming activity had a mean of 5.71, 4.69 and 3.47 SUV around the HA- and 5.04, 4.80 and 3.50 SUV around the PC-cups at 1 week, 4 months and 12 months respectively. Normal bone metabolism was 3.68 SUV. After 1 year activity had declined to normal levels for both groups. The clinical results were good in all cases. HA coating resulted in higher uptake indicating higher bone forming activity after 1 week. F-PET/CT is a valuable tool to analyse bone formation and secondary stabilisation of an acetabular cup.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-193322 (URN)10.5301/HIP.2012.9233 (DOI)000322980800008 ()22547382 (PubMedID)
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2017-12-06Bibliographically approved
Marsell, R., Sisask, G., Nilsson, Y., Sundgren-Andersson, A. K., Andersson, U., Larsson, S., . . . Jonsson, K. B. (2012). GSK-3 inhibition by an orally active small molecule increases bone mass in rats. Bone, 50(3), 619-627
Open this publication in new window or tab >>GSK-3 inhibition by an orally active small molecule increases bone mass in rats
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2012 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no 3, p. 619-627Article in journal (Refereed) Published
Abstract [en]

Glycogen synthase kinase 3β (GSK-3β) actions are central in the canonical Wnt pathway, important in many biological processes and a potential drug target for treating several diseases. It is appreciated that a balanced Wnt canonical signaling is crucial for the maintenance of normal bone mass. In this study we investigated the effects of a potent orally active GSK-3 inhibitor, AZD2858, on bone mass in rats. Treatment (1μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20mg/kg once daily (total BMC: 172% of control; p<0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p<0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20mg/kg once daily (Load at failure: 370% of control, p<0.001) and diaphyseal strength of femora subjected to a three point bending test (Load at failure: 115% of control; p<0.01). Furthermore, histomorphometry showed a dramatic increase in bone formation indices, and serum markers of both bone formation (Osteocalcin, 146% of control; p<0.001) and resorption (CTX, 189% of control; p<0.001) were elevated. Our conclusion is that a GSK-3 inhibitor drug may prove effective as an anabolic strategy in the treatment of diseases characterized by low bone mass, since AZD2858 has extensive bone building effects at predominantly trabecular sites.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-164308 (URN)10.1016/j.bone.2011.11.007 (DOI)000300650100006 ()22142634 (PubMedID)
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
Ullmark, G., Sundgren, K., Milbrink, J., Nilsson, O. & Sörensen, J. (2012). Metabolic development of necrotic bone in the femoral head following resurfacing arthroplasty: A clinical [(18)F]fluoride-PET study in 11 asymptomatic hips. Acta Orthopaedica, 83(1), 22-25
Open this publication in new window or tab >>Metabolic development of necrotic bone in the femoral head following resurfacing arthroplasty: A clinical [(18)F]fluoride-PET study in 11 asymptomatic hips
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2012 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 83, no 1, p. 22-25Article in journal (Refereed) Published
Abstract [en]

Background and purpose

One concern regarding resurfacing arthroplasty is the viability of the diminished femoral head and the postoperative risk of collapse, or a femoral neck fracture. (18)F-fluoride positron emission tomography (F-PET) enables us to assess bone viability despite there being a covering metal component. By F-PET studies, we recently showed the absence of metabolism in the remaining part of femoral heads, 1-4 years after surgery in 11 of 46 consecutive cases. We now present the further development of bone metabolism in these 11 cases.

Patients and methods

10 patients (11 chips) with previously shown loss of femoral head metabolism were evaluated by radiography and repeated F-PET scans, 3-6.5 years after surgery. The size of the area with low (18)F-fluoride PET uptake in the femoral head was compared to that in earlier PET images.

Results

No patients had any clinical symptoms; nor was any necrotic bone area visible in plain radiographs. On F-PET scans, 2 patients showed a diminished area with low uptake, 4 were unchanged, and 5 had enlarged areas.

Interpretation

Bone metabolism surrounding a volume of bone with no metabolic activity changes dynamically even 5 years after surgery. The presence of bone with minor uptake of F-tracer, indicating low or no bone metabolism, with further progression in 5 of 11 cases leads us to conclude that resurfacing THA should be used restrictively.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-164305 (URN)10.3109/17453674.2011.641108 (DOI)000300022600004 ()22112156 (PubMedID)
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
Lindqvist, A., Hjalmarsson, M. & Nilsson, O. (2011). DASH and Sollerman test scores after hand injury from powered wood splitters. Journal of Hand Surgery, European Volume, 36E(1), 57-61
Open this publication in new window or tab >>DASH and Sollerman test scores after hand injury from powered wood splitters
2011 (English)In: Journal of Hand Surgery, European Volume, ISSN 1753-1934, Vol. 36E, no 1, p. 57-61Article in journal (Refereed) Published
Abstract [en]

The purpose of the study was to describe the outcome after hand injury from powered wood splitters, and to investigate the relation between injury severity and outcome. Injury severity was rated according to the Hand Injury Severity Scoring System (HISS system) and the Injury Severity Score method. The patients were evaluated with the Disabilities of the Arm Shoulder and Hand outcome questionnaire (DASH), and 26 of the most severely injured patients were evaluated with the Sollerman test. The mean DASH score was moderately elevated at 15, indicating that many of these patients have sequelae. A statistically significant correlation between HISS and DASH scores was found, implying that initial injury severity is of importance for outcome. The mean Sollerman score in the injured hand was 66, which amounts to a significantly impaired hand function.

Keywords
log splitter, screw splitter, wedge splitter, consumer product related injury, occupational injury, agricultural injury, hand injury, child injury, vedklyv, hydraulklyv, skruvklyv, arbetsskada, handskada
National Category
Surgery Surgery Surgery Occupational Health and Environmental Health
Research subject
Plastic Surgery
Identifiers
urn:nbn:se:uu:diva-129395 (URN)10.1177/1753193410381820 (DOI)000286694000008 ()
Note
One reference (Lindqvist and Gerdin, 2008) is missing in the reference list.Available from: 2010-08-31 Created: 2010-08-14 Last updated: 2018-01-12Bibliographically approved
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