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Marsell, Richard
Publications (10 of 19) Show all publications
Hulsart Billström, G., Selvaraju, R., Estrada, S., Lubberink, M., Asplund, V., Bergman, K., . . . Antoni, G. (2018). Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept. Journal of Controlled Release, 285, 178-186
Open this publication in new window or tab >>Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept
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2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 285, p. 178-186Article in journal (Refereed) Published
Abstract [en]

Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.

Keywords
Bone morphogenetic protein 2, Bone tissue engineering, Hydrogel, Micro computed tomography, Positron emission tomography, Single-photon emission computed tomography
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-356465 (URN)10.1016/j.jconrel.2018.07.012 (DOI)000441737400015 ()30005906 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 262948
Note

G. Hulsart-Billström and R. K. Selvaraju contributed equally to this work and should be regarded as joint first authors.

Available from: 2018-07-28 Created: 2018-07-28 Last updated: 2018-10-10Bibliographically approved
Marsell, R. & Hailer, N. P. (2014). Successful treatment of a humeral capitulum osteonecrosis with bone morphogenetic protein-7 combined with autologous bone grafting. Upsala Journal of Medical Sciences, 119(3), 287-289
Open this publication in new window or tab >>Successful treatment of a humeral capitulum osteonecrosis with bone morphogenetic protein-7 combined with autologous bone grafting
2014 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 3, p. 287-289Article in journal (Refereed) Published
Abstract [en]

We present the case of a 27-year-old female with subcortical osteonecrosis of the humeral capitulum. Percutaneous retrograde drilling of the lesion and application of recombinant human bone morphogenetic protein (BMP)-7 were combined with autologous bone grafting. At follow-up the patient was almost pain-free, had normalized her range of motion, and radiography showed consolidation of the lesion without any heterotopic bone formation. By timing surgery prior to subchondral collapse, biomechanical stability of the subchondral bone was maintained. To our knowledge, this is the first report on the treatment of an osteonecrosis in this location with a BMP, and this strategy could potentially be applied in other locations with juxta-articular osteonecrosis.

Keywords
Bone graft, bone morphogenetic protein, elbow, osteochondritis dissecans, osteonecrosis
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-231224 (URN)10.3109/03009734.2014.931493 (DOI)000340110800010 ()25017508 (PubMedID)
Available from: 2014-09-08 Created: 2014-09-05 Last updated: 2017-12-05Bibliographically approved
Hulsart-Billström, G., Yuen, P. K., Marsell, R., Hilborn, J., Larsson, S. & Ossipov, D. (2013). Bisphosphonate-Linked Hyaluronic Acid Hydrogel Sequesters and Enzymatically Releases Active Bone Morphogenetic Protein-2 for Induction of Osteogenic Differentiation. Biomacromolecules, 14(9), 3055-3063
Open this publication in new window or tab >>Bisphosphonate-Linked Hyaluronic Acid Hydrogel Sequesters and Enzymatically Releases Active Bone Morphogenetic Protein-2 for Induction of Osteogenic Differentiation
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2013 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 9, p. 3055-3063Article in journal (Refereed) Published
Abstract [en]

Regeneration of bone by delivery of bone morphogenetic proteins (BMPs) from implantable scaffolds is a promising alternative to the existing autologous bone grafting procedures. Hydrogels are used extensively in biomaterials as delivery systems for different growth factors. However, a controlled release of the growth factors is necessary to induce bone formation, which can be accomplished by various chemical functionalities. Herein we demonstrate that functionalization of a hyaluronan (HA) hydrogel with covalently linked bisphosphonate (BP) ligands provides efficient sequestering of BMP-2 in the resulting HA-BP hydrogel. The HA-BP hydrogel was investigated in comparison with its analogue lacking BP groups (HA hydrogel). While HA hydrogel released 100% of BMP-2 over two weeks, less than 10% of BMP-2 was released from the HA-BP hydrogel for the same time. We demonstrate that the sequestered growth factor can still be released by enzymatic degradation of the HA-BP hydrogel. Most importantly, entrapment of BMP-2 in HA-BP hydrogel preserves the growth factor bioactivity, which was confirmed by induction of osteogenic differentiation of mesenchymal stem cells (MSCs) after the cells incubation with the enzymatic digest of the hydrogel. At the same time, the hydrogels degradation products were not toxic to MSCs and osteoblasts. Furthermore, BP-functionalization of HA hydrogels promotes adhesion of the cells to the surface of HA hydrogel. Altogether, the present findings indicate that covalent grafting of HA hydrogel with BP groups can alter the clinical effects of BMPs in bone tissue regeneration.

National Category
Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-219176 (URN)10.1021/bm400639e (DOI)000330095500012 ()
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2017-12-05Bibliographically 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
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
Mirza, M., Alsiö, J., Hammarstedt, A., Erben, R., Michaëlsson, K., Tivesten, Å., . . . Larsson, T. (2011). Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. Arteriosclerosis, Thrombosis and Vascular Biology, 31(1), 219-227
Open this publication in new window or tab >>Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals
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2011 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 31, no 1, p. 219-227Article in journal (Refereed) Published
Abstract [en]

Objective—Disturbances in mineral metabolism define an increased cardiovascular risk in patients with chronic kidney disease. Fibroblast growth factor-23 (FGF23) is a circulating regulator of phosphate and vitamin D metabolism and has recently been implicated as a putative pathogenic factor in cardiovascular disease. Because other members of the FGF family play a role in lipid and glucose metabolism, we hypothesized that FGF23 would associate with metabolic factors that predispose to an increased cardiovascular risk. The goal of this study was to investigate the relationship between FGF23 and metabolic cardiovascular risk factors in the community.

Methods and Results—Relationships between serum FGF23 and body mass index (BMI), waist circumference, waist-to-hip ratio, serum lipids, and fat mass were examined in 2 community-based, cross-sectional cohorts of elderly whites (Osteoporotic Fractures in Men Study: 964 men aged 75±3.2; Prospective Investigation of the Vasculature in Uppsala Seniors study: 946 men and women aged 70). In both cohorts, FGF23 associated negatively with high-density lipoprotein and apolipoprotein A1 (7% to 21% decrease per 1-SD increase in log FGF23; P<0.01) and positively with triglycerides (11% to 14% per 1-SD increase in log FGF23; P<0.01). A 1-SD increase in log FGF23 was associated with a 7% to 20% increase in BMI, waist circumference, and waist-to-hip ratio and a 7% to 18% increase in trunk and total body fat mass (P<0.01) as determined by whole-body dual x-ray absorptiometry. FGF23 levels were higher in subjects with the metabolic syndrome compared with those without (46.4 versus 41.2 pg/mL; P<0.05) and associated with an increased risk of having the metabolic syndrome (OR per 1-SD increase in log FGF23, 1.21; 95% CI, 1.04 to 1.40; P<0.05).

Conclusion—We report for the first time on associations between circulating FGF23, fat mass, and adverse lipid metabolism resembling the metabolic syndrome, potentially representing a novel pathway(s) linking high FGF23 to an increased cardiovascular risk.

Keywords
cardiovascular disease prevention, diabetes mellitus, elderly, epidemiology, FGF-23, FGF23, Fibroblast growth factor-23, growth factors, lipids, metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-130337 (URN)10.1161/ATVBAHA.110.214619 (DOI)000285342400033 ()20966399 (PubMedID)
Available from: 2010-09-06 Created: 2010-09-06 Last updated: 2017-12-12Bibliographically approved
Marsell, R. & Einhorn, T. A. (2011). The biology of fracture healing. Injury, 42(6), 551-555
Open this publication in new window or tab >>The biology of fracture healing
2011 (English)In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 42, no 6, p. 551-555Article in journal (Refereed) Published
Abstract [en]

The biology of fracture healing is a complex biological process that follows specific regenerative patterns and involves changes in the expression of several thousand genes. Although there is still much to be learned to fully comprehend the pathways of bone regeneration, the over-all pathways of both the anatomical and biochemical events have been thoroughly investigated. These efforts have provided a general understanding of how fracture healing occurs. Following the initial trauma, bone heals by either direct intramembranous or indirect fracture healing, which consists of both intramembranous and endochondral bone formation. The most common pathway is indirect healing, since direct bone healing requires an anatomical reduction and rigidly stable conditions, commonly only obtained by open reduction and internal fixation. However, when such conditions are achieved, the direct healing cascade allows the bone structure to immediately regenerate anatomical lamellar bone and the Haversian systems without any remodelling steps necessary. In all other non-stable conditions, bone healing follows a specific biological pathway. It involves an acute inflammatory response including the production and release of several important molecules, and the recruitment of mesenchymal stem cells in order to generate a primary cartilaginous callus. This primary callus later undergoes revascularisation and calcification, and is finally remodelled to fully restore a normal bone structure. In this article we summarise the basic biology of fracture healing. (C) 2011 Elsevier Ltd. All rights reserved.

Keywords
Bone healing, Intramembranous, Endochondral, Callus, Cartilaginous, Periosteal, Angiogenesis, Revascularisation, Bone trauma, Bone injury
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-155247 (URN)10.1016/j.injury.2011.03.031 (DOI)000291245800002 ()
Available from: 2011-06-21 Created: 2011-06-20 Last updated: 2017-12-11Bibliographically approved
Marsell, R. & Einhorn, T. A. (2010). Emerging bone healing therapies. Journal of Orthopaedic Trauma, 24(3, Suppl 1), S4-S8
Open this publication in new window or tab >>Emerging bone healing therapies
2010 (English)In: Journal of Orthopaedic Trauma, ISSN 0890-5339, E-ISSN 1531-2291, Vol. 24, no 3, Suppl 1, p. S4-S8Article in journal (Refereed) Published
Abstract [en]

Fracture healing is a biologically optimized process. Despite the expectation of unimpaired healing, approximately 5% to 10% of the 7.9 million fractures sustained annually in the United States have difficulty achieving union. Not only does this cause morbidity for patients, but also enormous healthcare and socioeconomic costs. Hence, there is a compelling need to find novel therapies to enhance fracture healing. In this article, we summarize current data on therapies to enhance skeletal healing and review their suggested biologic functions, proposed clinical applications, and known efficacies.

National Category
Surgery
Research subject
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-140865 (URN)10.1097/BOT.0b013e3181ca3fab (DOI)20182234 (PubMedID)
Available from: 2011-01-12 Created: 2011-01-10 Last updated: 2017-12-11Bibliographically approved
Marsell, R. & Jonsson, K. B. (2010). The phosphate regulating hormone fibroblast growth factor-23. Acta Physiologica, 200(2), 97-106
Open this publication in new window or tab >>The phosphate regulating hormone fibroblast growth factor-23
2010 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 200, no 2, p. 97-106Article, review/survey (Refereed) Published
Abstract [en]

Over the last decade, the regulation of phosphate (Pi) homeostasis has been under intense investigation. By utilizing modern biochemical and genetic tools, the pathophysiological mechanisms behind several known hereditary and acquired hypo- and hyperphosphatemic diseases have been clarified. The results of these efforts have opened new insights into the causes of Pi dysregulation and hereby also the physiological mechanisms determining Pi homeostasis. Although several potential Pi-regulating proteins have been discovered and investigated, current data strongly argues for fibroblast growth factor-23 (FGF23), a hormonal factor produced in bone, as a particularly important regulator of Pi homeostasis. In this article, we review the discovery of the FGF23 protein, as well as its biochemistry, localization of production, receptor specificity and mechanisms of action.

Keywords
fibroblast growth factor-23, osteomalacia, phosphate, parathyroid hormone, rickets
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-137705 (URN)10.1111/j.1748-1716.2010.02163.x (DOI)000281557700001 ()
Available from: 2010-12-16 Created: 2010-12-15 Last updated: 2017-12-11Bibliographically approved
Marsell, R., Mirza, M. A., Mallmin, H., Karlsson, M., Mellström, D., Orwoll, E., . . . Larsson, T. E. (2009). Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men. Osteoporosis International, 20(7), 1167-1173
Open this publication in new window or tab >>Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men
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2009 (English)In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 20, no 7, p. 1167-1173Article in journal (Refereed) Published
Abstract [en]

We evaluated the relation between serum FGF23 and bone mineral density (BMD) in a community-based cohort of elderly men. There was a weak correlation between FGF23 and BMD, which was primarily dependent on body weight.

INTRODUCTION: FGF23 is a hormonal factor produced in bone and regulates serum levels of phosphate (Pi) and vitamin D. FGF23 over-expression is associated with skeletal abnormalities, including rickets/osteomalacia. The relation between FGF23 and Bone Mineral Density (BMD) in the community remains unexplored.

METHODS: We employed a large, population-based cohort of 3014 Swedish men aged 69-80 years, without known renal disease. BMD was measured with dual X-ray absorptiometry (DXA) in the hip and lumbar spine. Serum intact FGF23 was analyzed with a two-site monoclonal ELISA.

RESULTS: There was a weak but significant correlation between FGF23 and BMD in femoral neck (r = 0.04, p < 0.05), femoral trochanter (r = 0.05, p = 0.004), total hip (r = 0.06, p = 0.0015) and lumbar spine (r = 0.07, p = 0.0004). The correlations remained significant when adjusting for biochemical covariates (Pi, calcium, PTH, 25(OH)D and renal function). However, the association became insignificant in all regions when adjusting for established confounding variables including age, height, weight and smoking. Further analysis confirmed a significant correlation between FGF23 and body weight (r = 0.13, p < 0.0001).

CONCLUSIONS: The weak correlation between FGF23 and BMD in elderly male subjects is mainly due to an association between FGF23 and body weight. Therefore, FGF23 may not play a significant role in the hormonal regulation of BMD.

Keywords
BMD, Bone densitometry, Bone mineralization, FGF-23, Fibroblast growth factor 23, Growth factors
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-98733 (URN)10.1007/s00198-008-0780-2 (DOI)000266665800008 ()18974917 (PubMedID)
Available from: 2010-01-26 Created: 2009-03-03 Last updated: 2017-12-13Bibliographically approved
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