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Fahlgren, Anna
Publications (10 of 29) Show all publications
Amirhosseini, M., Bernhardsson, M., Lång, P., Andersson, G., Flygare, J. & Fahlgren, A. (2019). Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.. Journal of Cellular Physiology, 234(9), 16503-16516
Open this publication in new window or tab >>Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.
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2019 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, no 9, p. 16503-16516Article in journal (Refereed) Published
Abstract [en]

Cyclin-dependent kinase 8 (CDK8) is a mediator complex-associated transcriptional regulator that acts depending on context and cell type. While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8-and its paralog CDK19-have been reported to affect the osteoblast lineage and bone formation. This study investigated the effects of two selective CDK8/19 inhibitors on osteoclastogenesis and osteoblasts in vitro, and further evaluated how local treatment with a CDK8/19 inhibitor affects cancellous bone healing in rats. CDK8/19 inhibitors did not alter the proliferation of neither mouse bone marrow-derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor κΒ (NF-κB) ligand (RANKL)-induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8/19, concomitant with reduced tartrate-resistant acid phosphatase (TRAP) activity and C-terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF-κB, nuclear factor of activated T-cells 1 (NFATc1), dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K in RANKL-stimulated BMMs. Downregulating RANK and its downstream signaling in osteoclast precursors enforce CDK8/19 inhibitors as anticatabolic agents to impede excessive osteoclastogenesis. In mouse primary osteoblasts, CDK8/19 inhibition did not affect differentiation but enhanced osteoblast mineralization by promoting alkaline phosphatase activity and downregulating osteopontin, a negative regulator of mineralization. In rat tibiae, a CDK8/19 inhibitor administered locally promoted cancellous bone regeneration. Our data indicate that inhibitors of CDK8/19 have the potential to develop into therapeutics to restrict osteolysis and enhance bone regeneration.

Keywords
CDK8, RANK, osteoblasts, osteoclasts
National Category
Cell and Molecular Biology Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-154927 (URN)10.1002/jcp.28321 (DOI)000470174200186 ()30793301 (PubMedID)
Note

Funding agencies: Vetenskapsradet [521-2013-2593, 2016-06097, K2015-99x-10363-23-4, 2016-01822]; Swedish Research Council

Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2019-07-03
Amirhosseini, M., Andersson, G., Aspenberg, P. & Fahlgren, A. (2017). Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening. Bone Reports, 7, 17-25
Open this publication in new window or tab >>Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening
2017 (English)In: Bone Reports, ISSN 2352-1872, Vol. 7, p. 17-25Article in journal (Refereed) Published
Abstract [en]

Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA). Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change = ± 1.5 and adjusted p-value = 0.05) at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL)-6, IL-1ß, chemokine (C-C motif) ligand (CCL)2, prostaglandin-endoperoxide synthase (Ptgs)2 and leukemia inhibitory factor (LIF) showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological and signaling pathways in this rat model for aseptic loosening. Pathways associated to the innate inflammatory response appear to be a major driver for osteolysis. Our findings implicate early restriction of inflammation to be critical to prevent or mitigate osteolysis and aseptic loosening of orthopedic implants.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Aseptic loosening; Implant; Instability; Microarray; Wear debris
National Category
Cell and Molecular Biology Orthopaedics
Identifiers
urn:nbn:se:liu:diva-146297 (URN)10.1016/j.bonr.2017.07.003 (DOI)28795083 (PubMedID)
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2019-03-08
Fahlgren, A., Bratengeier, C., Gelmi, A., Semeins, C. M., Klein-Nulend, J., Jager, E. & Bakker, A. D. (2015). Biocompatibility of Polypyrrole with Human Primary Osteoblasts and the Effect of Dopants. PLoS ONE, 10(7), Article ID e0134023.
Open this publication in new window or tab >>Biocompatibility of Polypyrrole with Human Primary Osteoblasts and the Effect of Dopants
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0134023Article in journal (Refereed) Published
Abstract [en]

Polypyrrole (PPy) is a conducting polymer that enables controlled drug release upon electrical stimulation. We characterized the biocompatibility of PPy with human primary osteoblasts, and the effect of dopants. We investigated the biocompatibility of PPy comprising various dopants, i.e. p-toluene sulfonate (PPy-pTS), chondroitin sulfate (PPy-CS), or dodecylbenzenesulfonate (PPy-DBS), with human primary osteoblasts. PPy-DBS showed the roughest appearance of all surfaces tested, and its wettability was similar to the gold-coated control. The average number of attached cells was 45% higher on PPy-DBS than on PPyCS or PPy-pTS, although gene expression of the proliferation marker Ki-67 was similar in osteoblasts on all surfaces tested. Osteoblasts seeded on PPy-DBS or gold showed similar vinculin attachment points, vinculin area per cell area, actin filament structure, and Ferets diameter, while cells seeded on PPY-CS or PPY-pTS showed disturbed focal adhesions and were enlarged with disorganized actin filaments. Osteoblasts grown on PPy-DBS or gold showed enhanced alkaline phosphatase activity and osteocalcin gene expression, but reduced osteopontin gene expression compared to cells grown on PPy-pTS and PPy-CS. In conclusion, PPy doped with DBS showed excellent biocompatibility, which resulted in maintaining focal adhesions, cell morphology, cell number, alkaline phosphatase activity, and osteocalcin gene expression. Taken together, conducting polymers doped with DBS are well tolerated by osteoblasts. Our results could provide a basis for the development of novel orthopedic or dental implants with controlled release of antibiotics and pharmaceutics that fight infections or focally enhance bone formation in a tightly controlled manner.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-120873 (URN)10.1371/journal.pone.0134023 (DOI)000358837700051 ()26225862 (PubMedID)
Note

Funding Agencies|VINNOVA [2012-04409]; Vetenskapradet [521-2013-2593]; Linkoping Initiative in Life Science Technologies (LIST)

Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2018-10-11
Grosso, M. J., Courtland, H.-W., Yang, X., Sutherland, J. P., Stoner, K., Nguyen, J., . . . Bostrom, M. P. (2015). Intermittent PTH Administration and Mechanical Loading Are Anabolic for Periprosthetic Cancellous Bone. Journal of Orthopaedic Research, 33(2), 163-173
Open this publication in new window or tab >>Intermittent PTH Administration and Mechanical Loading Are Anabolic for Periprosthetic Cancellous Bone
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2015 (English)In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 33, no 2, p. 163-173Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to determine the individual and combined effects on periprosthetic cancellous bone of intermittent parathyroid hormone administration (iPTH) and mechanical loading at the cellular, molecular, and tissue levels. Porous titanium implants were inserted bilaterally on the cancellous bone of adult rabbits beneath a loading device attached to the distal lateral femur. The left femur received a sham loading device. The right femur was loaded daily, and half of the rabbits received daily PTH. Periprosthetic bone was evaluated up to 28 days for gene expression, histology, and mu CT analysis. Loading and iPTH increased bone mass by a combination of two mechanisms: (1) Altering cell populations in a pro-osteoblastic/anti-adipocytic direction, and (2) controlling bone turnover by modulating the RANKL-OPG ratio. At the tissue level, BV/TV increased with both loading (+53%, pless than0.05) and iPTH (+54%, pless than0.05). Combined treatment showed only small additional effects at the cellular and molecular levels that corresponded to a small additive effect on bone volume (+13% compared to iPTH alone, pgreater than0.05). This study suggests that iPTH and loading are potential therapies for enhancing periprosthetic bone formation. The elucidation of the cellular and molecular response may help further enhance the combined therapy and related targeted treatment strategies.

Place, publisher, year, edition, pages
Wiley: 12 months, 2015
Keywords
implants; mechanical loading; intermittent PTH; periprosthetic bone mass
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-116840 (URN)10.1002/jor.22748 (DOI)000350472200002 ()25408434 (PubMedID)
Note

Funding Agencies|National Institutes of Health [R01-AR056802]; Clinical Translational Science Center [UL1-RR024996]

Available from: 2015-04-07 Created: 2015-04-07 Last updated: 2017-12-04
Nam, D., Bostrom, M. P. & Fahlgren, A. (2013). Emerging Ideas: Instability-induced Periprosthetic Osteolysis Is Not Dependent on the Fibrous Tissue Interface. Clinical Orthopaedics and Related Research, 471(6), 1758-1762
Open this publication in new window or tab >>Emerging Ideas: Instability-induced Periprosthetic Osteolysis Is Not Dependent on the Fibrous Tissue Interface
2013 (English)In: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 471, no 6, p. 1758-1762Article in journal (Refereed) Published
Abstract [en]

Stable initial fixation of a total joint arthroplasty implant is critical to avoid the risk of aseptic loosening and premature clinical failure. With implant motion, a fibrous tissue layer forms at the bone-implant interface, leading to implant migration and periprosthetic osteolysis. At the time of implant revision surgery, proresorptive signaling cytokines are expressed in the periimplant fibrous membrane. However, the exact role of this fibrous tissue in causing periprosthetic osteolysis attributable to instability remains unknown. less thanbrgreater than less thanbrgreater thanWe propose an alternative mechanism of periprosthetic osteolysis independent of the fibrous tissue layer, where pressurized fluid flow along the bone-implant interface activates mechanosensitive osteocytes in the periprosthetic bone, causing the release of proresorptive cytokines and subsequent osteoclast differentiation and osteolysis. less thanbrgreater than less thanbrgreater thanAn animal model for instability-induced osteolysis that mimics the periprosthetic bone-implant interface will be used. In this model, a fibrous tissue membrane is allowed to form in the periprosthetic zone, and pressurized fluid flow transmitted through this membrane reliably creates osteolytic lesions in the periprosthetic bone. In this study, half of the rats will have the fibrous tissue present, while the other half will not. We will determine whether the fibrous tissue membrane is essential for the release of proosteoclastic cytokines, leading to osteoclast differentiation and periprosthetic bone loss, by measuring the volume of bone resorption and presence of proresorptive cytokines at the bone-implant interface. less thanbrgreater than less thanbrgreater thanWe will determine whether the fibrous tissue membrane is crucial for osteoclastogenic signaling in the setting of periimplant osteolysis. In the future, this will allow us to test therapeutic interventions, such as specific cytokine inhibitors or alterations in implant design, which may translate into new, clinically relevant strategies to prevent osteolysis.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-93960 (URN)10.1007/s11999-013-2896-8 (DOI)000318511400006 ()
Note

Funding Agencies|Smith & Nephew Inc (Memphis, TN, USA)||Clinician Scientist Training Grant from the Orthopaedic Research and Education Foundation (Rosemont, IL, USA)||

Available from: 2013-06-13 Created: 2013-06-13 Last updated: 2017-12-06
Fahlgren, A., Yang, X., Ciani, C., Ryan, J. A., Kelly, N., Ko, F. C., . . . Boström, M. P. G. (2013). The effects of PTH, loading and surgical insult on cancellous bone at the bone-implant interface in the rabbit. Bone, 52(2), 718-724
Open this publication in new window or tab >>The effects of PTH, loading and surgical insult on cancellous bone at the bone-implant interface in the rabbit
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2013 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 52, no 2, p. 718-724Article in journal (Refereed) Published
Abstract [en]

Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone-implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the pen-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on pen-implant bone volume fraction. In this model, PTH enhanced pen-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced pen-implant bone volume, and surgery and PTH treatment had a strong combined effect This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Cancellous bone, Bone adaptation, Implant, PTH, Loading, Surgery
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88658 (URN)10.1016/j.bone.2012.05.005 (DOI)000313607700026 ()
Note

Funding Agencies|Orthopaedic Research and Education Foundation||National Institutes of Health|R01-AR056802R01-AG028664P30-AR046121|

Available from: 2013-02-14 Created: 2013-02-14 Last updated: 2017-12-06
Fahlgren, A., Johansson, L., Edlund, U. & Aspenberg, P. (2012). Direct ex vivo measurement of the fluid permeability of loose scar tissue. Acta of Bioengineering and Biomechanics, 14(2), 47-51
Open this publication in new window or tab >>Direct ex vivo measurement of the fluid permeability of loose scar tissue
2012 (English)In: Acta of Bioengineering and Biomechanics, ISSN 1509-409X, Vol. 14, no 2, p. 47-51Article in journal (Refereed) Published
Abstract [en]

Fluid flow is important in many biomechanical models, but there is a lack of experimental data that quantifies soft tissue permeability. We measured the tissue permeability in fibrous soft tissue, using a novel technique to obtain specimens by allowing soft tissue to grow into coralline hydroxyapatite scaffoldings implanted between the abdominal muscle layers of rats.

Place, publisher, year, edition, pages
Wroclaw, Poland: Wroclaw University of Technology, 2012
Keywords
permeability, Darcys law, soft tissue, hydraulic conductivity
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-93986 (URN)10.5277/abb120206 (DOI)000318777500006 ()
Available from: 2013-06-13 Created: 2013-06-13 Last updated: 2014-02-27Bibliographically approved
Nilsson, A., Norgard, M., Andersson, G. & Fahlgren, A. (2012). Fluid pressure induces osteoclast differentiation comparably to titanium particles but through a molecular pathway only partly involving TNFa. Journal of Cellular Biochemistry, 113(4), 1224-1234
Open this publication in new window or tab >>Fluid pressure induces osteoclast differentiation comparably to titanium particles but through a molecular pathway only partly involving TNFa
2012 (English)In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 113, no 4, p. 1224-1234Article in journal (Refereed) Published
Abstract [en]

In contrast to the well-understood inflammatory pathway driven by TNFa, by which implant-derived particles induce bone resorption, little is known about the process in which loosening is generated as a result of force-induced mechanical stimulus at the boneimplant interface. Specifically, there is no knowledge as to what cells or signaling pathways couple mechanical stimuli to bone resorption in context of loosening. We hypothesized that different stimuli, i.e., fluid flow versus wear particles, act through different cytokine networks for activation and localization of osteoclasts. By using an animal model in which osteoclasts and bone resorption were induced by fluid pressure or particles, we were able to detect distinct differences in osteoclast localization and inflammatory gene expression between fluid pressure and titanium particles. Fluid pressure recruits and activates osteoclasts with bone marrow contact away from the fluid pressure exposure zone, whereas titanium particles recruit and activate osteoclasts in areas in direct contact to particles. Fluid pressure induced weaker expression of the selected inflammatory related genes, although the eventual degree of osteoclast induction was similar in both models. Using TNFaRa (4?mg/kg) (Enbrel) and dexamethasone (2?mg/kg) as specific and more general suppressors of inflammation we showed that the TNFaRa failed to generate statistically impaired osteoclast generation while dexamethasone was much more potent. These results demonstrate that fluid pressure induces osteoclasts at a different localization than titanium particles by a molecular pathway less associated with TNFa and the innate system, which open up for other pathways controlling pressure induced osteoclastogenesis.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keywords
PRESSURE; FLOW; OSTEOCLASTOGENESIS; CYTOKINES; OSTEOLYSIS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86565 (URN)10.1002/jcb.23456 (DOI)000300719000016 ()
Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2017-12-06
Fahlgren, A., Nilsson, A., Norgard, M. & Andersson, G. (2011). FLUID PRESSURE AND TITANIUM PARTICLES INDUCES OSTEOCLAST ACTIVATION VIA ALTERNATIVE PATHWAYS in OSTEOPOROSIS INTERNATIONAL, vol 22, issue , pp 33-33. In: OSTEOPOROSIS INTERNATIONAL (pp. 33-33). Springer Science Business Media, 22
Open this publication in new window or tab >>FLUID PRESSURE AND TITANIUM PARTICLES INDUCES OSTEOCLAST ACTIVATION VIA ALTERNATIVE PATHWAYS in OSTEOPOROSIS INTERNATIONAL, vol 22, issue , pp 33-33
2011 (English)In: OSTEOPOROSIS INTERNATIONAL, Springer Science Business Media , 2011, Vol. 22, p. 33-33Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Springer Science Business Media, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68339 (URN)000288662000054 ()
Available from: 2011-05-20 Created: 2011-05-20 Last updated: 2012-03-22
Johansson, L., Edlund, U., Fahlgren, A. & Aspenberg, P. (2011). Fluid-induced osteolysis: modelling and experiments. COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING, 14(4), 305-318
Open this publication in new window or tab >>Fluid-induced osteolysis: modelling and experiments
2011 (English)In: COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING, ISSN 1025-5842, Vol. 14, no 4, p. 305-318Article in journal (Refereed) Published
Abstract [en]

A model to calculate bone resorption driven by fluid flow at the bone-soft tissue interface is developed and used as a basis for computer calculations, which are compared to experiments where bone is subjected to fluid flow in a rat model. Previous models for bone remodelling calculations have been based on the state of stress, strain or energy density of the bone tissue as the stimulus for remodelling. We believe that there is experimental support for an additional pathway where an increase in the amount of the cells directly involved in bone removal, the osteoclasts, is caused by fluid pressure, flow velocity or other parameters related to fluid flow at the bone-soft tissue interface, resulting in bone resorption.

Place, publisher, year, edition, pages
Taylor and Francis, 2011
Keywords
bone resorption, theory of mixtures, experimental model, finite element method
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67561 (URN)10.1080/10255842.2010.484808 (DOI)000288951800001 ()
Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2012-03-22
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