| 1. |
- Amirhosseini, Mehdi, et al.
(författare)
-
Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.
- 2019
-
Ingår i: Journal of Cellular Physiology. - : Wiley. - 0021-9541 .- 1097-4652. ; 234:9, s. 16503-16516
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 2. |
- Bergwik, Jesper, et al.
(författare)
-
Macrophage expressed tartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis progression
- 2024
-
Ingår i: Immunology. - 0019-2805. ; 171:4, s. 583-594
-
Tidskriftsartikel (refereegranskat)abstract
- Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder involving scarring of pulmonary tissue and a subsequent decrease in respiratory capacity, ultimately resulting in death. Tartrate resistant acid phosphatase 5 (ACP5) plays a role in IPF but the exact mechanisms are yet to be elucidated. In this study, we have utilized various perturbations of the bleomycin mouse model of IPF including genetic knockout, RANKL inhibition, and macrophage adoptive transfer to further understand ACP5's role in pulmonary fibrosis. Genetic ablation of Acp5 decreased immune cell recruitment to the lungs and reduced the levels of hydroxyproline (reflecting extracellular matrix-production) as well as histological damage. Additionally, gene expression profiling of murine lung tissue revealed downregulation of genes including Ccl13, Mmp13, and Il-1α that encodes proteins specifically related to immune cell recruitment and macrophage/fibroblast interactions. Furthermore, antibody-based neutralization of RANKL, an important inducer of Acp5 expression, reduced immune cell recruitment but did not decrease fibrotic lung development. Adoptive transfer of Acp5 -/- bone marrow-derived monocyte (BMDM) macrophages 7 or 14 days after bleomycin administration resulted in reductions of cytokine production and decreased levels of lung damage, compared to adoptive transfer of WT control macrophages. Taken together, the data presented in this study suggest that macrophage derived ACP5 plays an important role in development of pulmonary fibrosis and could present a tractable target for therapeutic intervention in IPF.
|
|
| 3. |
- Johansson, Pernilla, et al.
(författare)
-
How well do mould models predict mould growth in buildings, considering the end-user perspective?
- 2021
-
Ingår i: Journal of Building Engineering. - : Elsevier Ltd. - 2352-7102. ; 40
-
Tidskriftsartikel (refereegranskat)abstract
- Mould growth results from a complex interaction between environmental factors, material properties, and mould fungi characteristics. These interactions must be considered during the design, construction and maintenance of a building to prevent growth. Mould prediction models aim to predict whether mould will grow on a specific material in a part of building with a known, or simulated, relative humidity and temperature. They are often used in the design phase. Several models are available. There is limited research on the performance of the models in real buildings. This study aimed to evaluate six different models, using data from five building parts. The predictions on whether mould growth was expected or not were compared to actual mould growth observations on five building materials. The study was performed as a round-robin. Most models underestimated the possibility for mould when humidity and temperature varied a lot by time. The outcome also depended on the end-user, who needs to make assumptions and parameter values choices on, for example, material susceptibility for mould growth. Therefore, using the same climate data, mould growth prediction may differ depending on who makes the prediction. One model, MOGLI model, where input data comes from laboratory tests and no such assumptions must be made, predicted correct in most cases. One conclusion of the study is that when predictions are made in practice, the results must be used cautiously. More knowledge is needed to understand, and more accurately model, the relationships between the moisture and temperature variations in buildings and the risk for mould growth.
|
|
| 4. |
- Johansson, Pernilla, et al.
(författare)
-
Kritiskt fukttillstånd för mögelpåväxt på byggnadsmaterial
- 2022
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Critical moisture level for mould growth on building materials. Mould can grow on building materials in 75-100% relative humidity (RH) at room temperature. How sensitive materials are to mould growth varies. One way to describe this sensitivity is the critical moisture level, RHcrit, the lowest RH at which mould can grow on a material. The critical moisture level for different material groups was proposed based on the current research situation in 2005, in the report ” Microbiological growth on building materials – critical moisture levels. State of the art” (SP Rapport 2005: 11). Based on new research results, these values are no longer valid. This report provides a general overview of the conditions for mould growth on building materials, focusing on the critical moisture level and the new research results. The main conclusion is that RHcrit is a product-specific property. It is impossible to estimate RHcrit for a product based on that it belongs to a group of materials, such as plaster or wood-based boards. Instead, RHcrit must be determined by laboratory tests for each product. The report also discusses how the results of a laboratory test can be used to prevent mould growth in buildings with known RF and temperature and the benefits of using RHcrit instead of traditional mould resistance tests.
|
|
| 5. |
- Johansson, Pernilla, et al.
(författare)
-
Threshold values for mould growth : Critical moisture level of 21 different building materials
- 2020
-
Ingår i: E3S Web of Conferences. Volume 172, 2020. - : EDP Sciences.
-
Konferensbidrag (refereegranskat)abstract
- The susceptibility for mould growth varies among different building materials. One way to describe the susceptibility is the lowest RH at which mould can grow on a specific material, the critical moisture level (RHcrit). Determining RHcrit for materials provide the basis for material choice in designs where moisture and temperature conditions are known. In this study, RHcrit of 21different products were determined according to SIS-TS 41:2014/SPMet 4927. This test method is developed based on the results of a variety of laboratory studies and validated by field studies. Test specimens were inoculated with a suspension containing spores from six different mould fungi and were then incubated in moisture chambers at four levels of RH at 22 °C. After 12 weeks specimens were analysed for mould growth. RHcrit was determined based on the lowest RH at which mould grew on the specimens. RHcrit varied among different products, even between product belonging to a similar group of material, for example, calcium silicate boards or gypsum boards. The results show, and confirm, previous findings that it is not possible to estimate RHcrit for a specific product based on material group. Instead, each product must be tested. © The Authors
|
|
| 6. |
- Lång, Pernilla
(författare)
-
Tartrate resistant acid phosphatase in the immune and nervous system : distribution and pathophysiological implications
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tartrate resistant acid phosphatase (TRAP) belongs to the family of purple acid phosphatases (PAP). It is a glycoprotein synthesized as a monomer with low enzyme activity containing a redox active diiron centre in the active site. Post-translational proteolytic processing of this monomer into a dimeric protein increases the enzyme activity. Traditionally, TRAP has been used as a marker for bone resorbing cells but the biological function of TRAP is still not fully elucidated. However, some studies suggested that also cells outside the skeleton express TRAP and consequently the distribution, characterization and possible functions of TRAP outside the skeleton were addressed in this thesis. Our results show that resident and inflammatory macrophages, certain neurons and epithelial cells express TRAP. Biochemical characterization of extra skeletal TRAPs showed that they contain a redox active di-iron centre, and that proteolytic processing seems to be important for the reduction of this centre. Monomeric TRAP tended to be more highly expressed in epithelial cells compared to cells of the myeloid lineage, but, subpopulations of macrophages i.e. alveolar macrophages and adipose tissue macrophages isolated from hyperplastic obesity also seems to express high amounts of monomeric TRAP. With respect to possible physiological functions, monomeric TRAP was shown stimulate proliferation and differentiation of adipocytes. High expression of monomeric TRAP in human obese adipose tissue macrophages suggests a role of macrophage-derived monomeric TRAP in the development of hyperplastic obesity associated with normal insulin sensitivity and normal lipid- and carbohydrate-metabolism in adipocytes. In macrophages, Th1 cytokines and lipopolysaccaride (LPS) up regulated TRAP expression. Induction of TRAP expression in the early stages of experimental DSS-induced colitis in rats suggests that TRAP could be utilized as a cellular marker of Th1-dependent macrophage activation in inflammatory bowel diseases. In summary, macrophages, certain epithelial cells and neurons express TRAP. Taking into account organ size, the largest contributors of TRAP are bone, spleen and liver. The differential expression of monomeric and proteolytically processed TRAP in a macrophage cell population could influence the biological effects of TRAP to act either as a growth factor or as a modulator of innate immune responses in certain inflammatory conditions.
|
|
| 7. |
- Tanner, Lloyd, et al.
(författare)
-
Tartrate resistant acid phosphatase 5 (TRAP5) mediates immune cell recruitment in a murine model of pulmonary bacterial infection
- 2022
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: During airway infection, upregulation of proinflammatory cytokines and subsequent immune cell recruitment is essential to mitigate bacterial infection. Conversely, during prolonged and non-resolving airway inflammation, neutrophils contribute to tissue damage and remodeling. This occurs during diseases including cystic fibrosis (CF) and COPD where bacterial pathogens, not least Pseudomonas aeruginosa, contribute to disease progression through long-lasting infections. Tartrate-resistant acid phosphatase (TRAP) 5 is a metalloenzyme expressed by alveolar macrophages and one of its target substrates is the phosphoglycoprotein osteopontin (OPN).Methods: We used a knockout mouse strain (Trap5-/-) and BALB/c-Tg (Rela-luc)31Xen mice paired with siRNA administration or functional protein add-back to elucidate the role of Trap5 during bacterial infection. In a series of experiments, Trap5-/- and wild-type control mice received intratracheal administration of P.aerugniosa (Xen41) or LPS, with mice monitored using intravital imaging (IVIS). In addition, multiplex cytokine immunoassays, flow cytometry, multispectral analyses, histological staining were performed.Results: In this study, we found that Trap5-/- mice had impaired clearance of P. aeruginosa airway infection and reduced recruitment of immune cells (i.e. neutrophils and inflammatory macrophages). Trap5 knockdown using siRNA resulted in a decreased activation of the proinflammatory transcription factor NF-κB in reporter mice and a subsequent decrease of proinflammatory gene expression. Add-back experiments of enzymatically active TRAP5 to Trap5-/- mice restored immune cell recruitment and bacterial killing. In human CF lung tissue, TRAP5 of alveolar macrophages was detected in proximity to OPN to a higher degree than in normal lung tissue, indicating possible interactions.Discussion: Taken together, the findings of this study suggest a key role for TRAP5 in modulating airway inflammation. This could have bearing in diseases such as CF and COPD where excessive neutrophilic inflammation could be targeted by pharmacological inhibitors of TRAP5.
|
|
