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- Maccarana, Marco, et al.
(författare)
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Dermatan Sulfate Epimerase 1-Deficient Mice have Reduced Content and Changed Distribution of Iduronic acids in Dermatan Sulfate and an Altered Collagen Structure in Skin.
- 2009
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Ingår i: Molecular and Cellular Biology. - 0270-7306. ; 29, s. 5517-5528
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Tidskriftsartikel (refereegranskat)abstract
- Dermatan sulfate epimerase 1 (DS-epi1) and 2 convert glucuronic acid to iduronic acid in chondroitin/dermatan sulfate biosynthesis. Here we report on the generation of DS-epi1-null mice and the resulting alterations in the chondroitin/dermatan polysaccharide chains. The numbers of long blocks of adjacent iduronic acids are greatly decreased in skin decorin and biglycan chondroitin/dermatan sulfate, along with a parallel decrease of iduronic-2-O-sulfated-galactosamine-4-O-sulfated structures. Both iduronic acid blocks and iduronic acids surrounded by glucuronic acids are also decreased in versican-derived chains. DS-epi1-deficient mice are smaller than wild-type littermates, but otherwise have no gross macroscopic alterations. The lack of DS-epi1 affects the chondroitin/dermatan sulfate in many proteoglycans and the consequences for skin collagen structure were initially analyzed. We found that the skin collagen architecture was altered, and electron microscopy showed that the DS-epi1-null fibrils have a larger diameter than the wild-type fibrils. The altered chondroitin/dermatan sulfate chains carried by decorin in skin are likely to affect the collagen fibril formation and reduce the tensile strength of DS-epi1-null skin.
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- Olof Olsson, P., et al.
(författare)
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Inhibition of integrin αvβ6 changes fibril thickness of stromal collagen in experimental carcinomas
- 2018
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Ingår i: Cell Communication and Signaling. - : Springer Science and Business Media LLC. - 1478-811X. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF-β1 and -β3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma. Methods: The potential role of αVβ6 integrin-mediated activation of latent TGF-β was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal αVβ6 integrin-specific monoclonal antibody 3G9 was used to inhibit the αVβ6 integrin activity. Results: Both KAT-4 and Capan-2 cells expressed the αVβ6 integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-β in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-β1 and -β3 reduced collagen fibril thickness in both tumor models. Conclusion: Our data demonstrate that the αVβ6-directed activation of latent TGF-β plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to αVβ6 inhibition depends on the simultaneous presence of alternative paths for latent TGF-β activation and the extent of desmoplasia.
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- Olsson, P. Olof, et al.
(författare)
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Inhibition of integrin alpha(V)beta(6) changes fibril thickness of stromal collagen in experimental carcinomas
- 2018
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Ingår i: Cell Communication and Signaling. - : BMC. - 1478-811X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF beta 1 and -beta 3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma.Methods: The potential role of a(v)beta(6) integrin-mediated activation of latent TGF-beta was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal a(v)beta(6) integrin-speafic monoclonal antibody 3G9 was used to inhibit the a(v)beta(6) integrin activity.Results: Both KAT-4 and Capan-2 cells expressed the a(v)beta(6) integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-beta in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-beta 1 and -beta 3 reduced collagen fibril thickness in both tumor models.Conclusion: Our data demonstrate that the a(v)beta(6)-directed activation of latent TGF-beta plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to a(v)beta(6) inhibition depends on the simultaneous presence of alternative paths for latent TGF-beta activation and the extent of desmoplasia.
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- Sequeros, C.B., et al.
(författare)
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A genome-wide association study of social trust in 33,882 Danish blood donors
- 2024
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Ingår i: Scientific Reports. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Social trust is a heritable trait that has been linked with physical health and longevity. In this study, we performed genome-wide association studies of self-reported social trust in n = 33,882 Danish blood donors. We observed genome-wide and local evidence of genetic similarity with other brain-related phenotypes and estimated the single nucleotide polymorphism-based heritability of trust to be 6% (95% confidence interval = (2.1, 9.9)). In our discovery cohort (n = 25,819), we identified one significantly associated locus (lead variant: rs12776883) in an intronic enhancer region of PLPP4, a gene highly expressed in brain, kidneys, and testes. However, we could not replicate the signal in an independent set of donors who were phenotyped a year later (n = 8063). In the subsequent meta-analysis, we found a second significantly associated variant (rs71543507) in an intergenic enhancer region. Overall, our work confirms that social trust is heritable, and provides an initial look into the genetic factors that influence it.
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- Tillgren, Viveka, et al.
(författare)
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Novel Small Leucine-Rich Protein Chondroadherin-like (CHADL) is Expressed in Cartilage and Modulates Chondrocyte Differentiation.
- 2015
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 290:2, s. 918-925
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Tidskriftsartikel (refereegranskat)abstract
- The constitution and biophysical properties of extracellular matrices can dramatically influence cellular phenotype during development, homeostasis, or pathogenesis. These effects can be signaled through a differentially regulated assembly of collagen fibrils, orchestrated by a family of collagen-associated Small Leucine-Rich Proteins, SLRPs. In this report, we describe the tissue-specific expression and function of a previously uncharacterized SLRP Chondroadherin-like (CHADL). We have developed antibodies against CHADL and, by immunohistochemistry, detected CHADL expression mainly in skeletal tissues, particularly in fetal cartilage and in pericellular space of adult chondrocytes. In situ hybridizations and immunoblots on tissue lysates confirmed this tissue-specific expression pattern. Recombinant CHADL bound collagen in cell culture, and inhibited in vitro collagen fibrillogenesis. After Chadl shRNA knockdown chondrogenic ATDC5 cells increased their proliferation and differentiation, indicated by increased transcript levels of Sox9, Ihh, Col2a1, and Col10a1. The knockdown increased collagen II and aggrecan deposition in the cell layers. Microarray analysis of the knockdown samples suggested collagen receptor-related changes, although other upstream effects could not be excluded. Together, our data indicate that the novel SLRP CHADL is expressed in cartilaginous tissues, influences collagen fibrillogenesis, and modulates chondrocyte proliferation and differentiation. CHADL appears to have a negative regulatory role, possibly ensuring the formation of a stable extracellular matrix.
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