Membrane-associated collagens with interrupted triple-helices (MACITs):evolution from a bilaterian common ancestor and functional conservation <i>in C. elegans</i>

Protein sequence alignment of human collagens XIII, XXIII, XXV and six alternative spliced variants of COL-99. The protein sequence of the newly identified COL-99f was compared with the other COL-99 variants and human collagens XIII, XXIII and XXV. Putative furin cleavage residues in these proteins and the peptides for producing the COL-99 antibodies AB5625.11 and AB693 are highlighted in the sequence. (PDF 22 kb

Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is one of the most common metastatic skin cancers with increasing incidence. We examined the roles of complement component C3 and complement factor B (CFB) in the growth of cSCC. Analysis of cSCC cell lines (n = 8) and normal human epidermal kerati-nocytes (n = 11) with real-time quantitative PCR and Western blotting revealed up-regulation of C3 and CFB expression in cSCC cells. Immunohistochemical staining revealed stronger tumor cell specific Labeling for C3 and CFB in invasive cSCCs (n = 71) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n = 11) than in cSCC in situ (n = 69), actinic keratoses (n = 63), and normal skin (n = 5). Significant up-regulation of C3 and CFB mRNA expression was noted in chemically induced mouse cSCCs, compared to benign papillomas. Knockdown of C3 and CFB expression inhibited migration and proliferation of cSCC cells and resulted in potent inhibition of extracellular signal regulated kinase 1/2 activation. Knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the rotes of C3 and CFB in the development of cSCC and identify them as biomarkers and potential therapeutic targets in this metastatic skin cancer.Peer reviewe

Redox-fibrosis : Impact of TGFβ1 on ROS generators, mediators and functional consequences

AbstractFibrosis is one of the most prevalent features of age-related diseases like obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease, or cardiomyopathy and affects millions of people in all countries. Although the understanding about the pathophysiology of fibrosis has improved a lot during the recent years, a number of mechanisms still remain unknown. Although TGF-β1 signaling, loss of metabolic homeostasis and chronic low-grade inflammation appear to play important roles in the pathogenesis of fibrosis, recent evidence indicates that oxidative stress and the antioxidant system may also be crucial for fibrosis development and persistence. These findings point to a concept of a redox-fibrosis where the cellular oxidant and antioxidant system could be potential therapeutic targets. The current review aims to summarize the existing links between TGF-β1 signaling, generation and action of reactive oxygen species, expression of antioxidative enzymes, and functional consequences including epigenetic redox-mediated responses during fibrosis.Abstract Fibrosis is one of the most prevalent features of age-related diseases like obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease, or cardiomyopathy and affects millions of people in all countries. Although the understanding about the pathophysiology of fibrosis has improved a lot during the recent years, a number of mechanisms still remain unknown. Although TGF-β1 signaling, loss of metabolic homeostasis and chronic low-grade inflammation appear to play important roles in the pathogenesis of fibrosis, recent evidence indicates that oxidative stress and the antioxidant system may also be crucial for fibrosis development and persistence. These findings point to a concept of a redox-fibrosis where the cellular oxidant and antioxidant system could be potential therapeutic targets. The current review aims to summarize the existing links between TGF-β1 signaling, generation and action of reactive oxygen species, expression of antioxidative enzymes, and functional consequences including epigenetic redox-mediated responses during fibrosis

Toward understanding scarless skin wound healing and pathological scarring [version 1; peer review: 2 approved]

AbstractThe efficient healing of skin wounds is crucial for securing the vital barrier function of the skin, but pathological wound healing and scar formation are major medical problems causing both physiological and psychological challenges for patients. A number of tightly coordinated regenerative responses, including haemostasis, the migration of various cell types into the wound, inflammation, angiogenesis, and the formation of the extracellular matrix, are involved in the healing process. In this article, we summarise the central mechanisms and processes in excessive scarring and acute wound healing, which can lead to the formation of keloids or hypertrophic scars, the two types of fibrotic scars caused by burns or other traumas resulting in significant functional or aesthetic disadvantages. In addition, we discuss recent developments related to the functions of activated fibroblasts, the extracellular matrix and mechanical forces in the wound environment as well as the mechanisms of scarless wound healing. Understanding the different mechanisms of wound healing is pivotal for developing new therapies to prevent the fibrotic scarring of large skin wounds.Abstract The efficient healing of skin wounds is crucial for securing the vital barrier function of the skin, but pathological wound healing and scar formation are major medical problems causing both physiological and psychological challenges for patients. A number of tightly coordinated regenerative responses, including haemostasis, the migration of various cell types into the wound, inflammation, angiogenesis, and the formation of the extracellular matrix, are involved in the healing process. In this article, we summarise the central mechanisms and processes in excessive scarring and acute wound healing, which can lead to the formation of keloids or hypertrophic scars, the two types of fibrotic scars caused by burns or other traumas resulting in significant functional or aesthetic disadvantages. In addition, we discuss recent developments related to the functions of activated fibroblasts, the extracellular matrix and mechanical forces in the wound environment as well as the mechanisms of scarless wound healing. Understanding the different mechanisms of wound healing is pivotal for developing new therapies to prevent the fibrotic scarring of large skin wounds

Toward understanding scarless skin wound healing and pathological scarring

The efficient healing of skin wounds is crucial for securing the vital barrier function of the skin, but pathological wound healing and scar formation are major medical problems causing both physiological and psychological challenges for patients. A number of tightly coordinated regenerative responses, including haemostasis, the migration of various cell types into the wound, inflammation, angiogenesis, and the formation of the extracellular matrix, are involved in the healing process. In this article, we summarise the central mechanisms and processes in excessive scarring and acute wound healing, which can lead to the formation of keloids or hypertrophic scars, the two types of fibrotic scars caused by burns or other traumas resulting in significant functional or aesthetic disadvantages. In addition, we discuss recent developments related to the functions of activated fibroblasts, the extracellular matrix and mechanical forces in the wound environment as well as the mechanisms of scarless wound healing. Understanding the different mechanisms of wound healing is pivotal for developing new therapies to prevent the fibrotic scarring of large skin wounds.publishedVersio

Pan-Cancer analysis of the expression and regulation of matrisome genes across 32 tumor types

AbstractThe microenvironment plays a central role in cancer, and neoplastic cells actively shape it to their needs by complex arrays of extracellular matrix (ECM) proteins, enzymes, cytokines and growth factors collectively referred to as the matrisome. Studies on the cancer matrisome have been performed for single or few neoplasms, but a more systematic analysis is still missing. Here we present a Pan-Cancer study of matrisome gene expression in 10,487 patients across 32 tumor types, supplemented with transcription factors (TFs) and driver genes/pathways regulating each tumor’s matrisome. We report on 919 TF-target pairs, either used specifically or shared across tumor types, and their prognostic significance, 40 master regulators, 31 overarching regulatory pathways and the potential for druggability with FDA-approved cancer drugs. These results provide a comprehensive transcriptional architecture of the cancer matrisome and suggest the need for development of specific matrisome-targeting approaches for future therapies.Abstract The microenvironment plays a central role in cancer, and neoplastic cells actively shape it to their needs by complex arrays of extracellular matrix (ECM) proteins, enzymes, cytokines and growth factors collectively referred to as the matrisome. Studies on the cancer matrisome have been performed for single or few neoplasms, but a more systematic analysis is still missing. Here we present a Pan-Cancer study of matrisome gene expression in 10,487 patients across 32 tumor types, supplemented with transcription factors (TFs) and driver genes/pathways regulating each tumor’s matrisome. We report on 919 TF-target pairs, either used specifically or shared across tumor types, and their prognostic significance, 40 master regulators, 31 overarching regulatory pathways and the potential for druggability with FDA-approved cancer drugs. These results provide a comprehensive transcriptional architecture of the cancer matrisome and suggest the need for development of specific matrisome-targeting approaches for future therapies

Collagens Regulating Adipose Tissue Formation and Functions

AbstractThe globally increasing prevalence of obesity is associated with the development of metabolic diseases such as type 2 diabetes, dyslipidemia, and fatty liver. Excess adipose tissue (AT) often leads to its malfunction and to a systemic metabolic dysfunction because, in addition to storing lipids, AT is an active endocrine system. Adipocytes are embedded in a unique extracellular matrix (ECM), which provides structural support to the cells as well as participating in the regulation of their functions, such as proliferation and differentiation. Adipocytes have a thin pericellular layer of a specialized ECM, referred to as the basement membrane (BM), which is an important functional unit that lies between cells and tissue stroma. Collagens form a major group of proteins in the ECM, and some of them, especially the BM-associated collagens, support AT functions and participate in the regulation of adipocyte differentiation. In pathological conditions such as obesity, AT often proceeds to fibrosis, characterized by the accumulation of large collagen bundles, which disturbs the natural functions of the AT. In this review, we summarize the current knowledge on the vertebrate collagens that are important for AT development and function and include basic information on some other important ECM components, principally fibronectin, of the AT. We also briefly discuss the function of AT collagens in certain metabolic diseases in which they have been shown to play central roles.Abstract The globally increasing prevalence of obesity is associated with the development of metabolic diseases such as type 2 diabetes, dyslipidemia, and fatty liver. Excess adipose tissue (AT) often leads to its malfunction and to a systemic metabolic dysfunction because, in addition to storing lipids, AT is an active endocrine system. Adipocytes are embedded in a unique extracellular matrix (ECM), which provides structural support to the cells as well as participating in the regulation of their functions, such as proliferation and differentiation. Adipocytes have a thin pericellular layer of a specialized ECM, referred to as the basement membrane (BM), which is an important functional unit that lies between cells and tissue stroma. Collagens form a major group of proteins in the ECM, and some of them, especially the BM-associated collagens, support AT functions and participate in the regulation of adipocyte differentiation. In pathological conditions such as obesity, AT often proceeds to fibrosis, characterized by the accumulation of large collagen bundles, which disturbs the natural functions of the AT. In this review, we summarize the current knowledge on the vertebrate collagens that are important for AT development and function and include basic information on some other important ECM components, principally fibronectin, of the AT. We also briefly discuss the function of AT collagens in certain metabolic diseases in which they have been shown to play central roles

Haavan paraneminen ja arpeutumisen häiriöt

TiivistelmäIhohaavan nopea paraneminen on yksilön selviytymisen kannalta ratkaisevaa ihon elintärkeän suojaustehtävän vuoksi. Haavan paranemiseen liittyy useita kudosta korjaavia biologisia vasteita kuten hemostaasi, tulehdus, erilaisten solujen migraatio haava-alueelle, niiden jakautuminen ja erilaistuminen, angiogeneesi sekä sidekudoksen muodostus ja muokkaus. Häiriöt näissä tapahtumissa johtavat haavan kroonistumiseen tai liiallisen arpikudoksen muodostumiseen. Tarkastelemme akuutin haavan paranemisen vaiheita sekä arpeutumisen häiriöitä eli hypertrofisia arpia ja keloideja, jotka voivat aiheuttaa merkittävää toiminnallista ja kosmeettista haittaa. Haavan paranemiseen ja arven muodostumiseen liittyvien solu- ja molekyylitason mekanismien ymmärtäminen on ensiarvoisen tärkeää kehiteltäessä uusia hoitomenetelmiä palovammoista tai muista traumoista johtuvien laajojen ihoalueiden arpeutumisen ehkäisemiseen.SummaryWound healing and pathological scarringEfficient healing of skin wounds is crucial because of the vital barrier function of the skin. Multiple tightly coordinated regenerative responses are involved in the healing process, including hemostasis, migration of various cell types into the wound, inflammation, angiogenesis, and formation of the extracellular matrix. This review summarizes the phases of acute wound healing and excessive scarring which can lead to formation of hypertrophic scars or keloids, the two types of fibrotic scars that can cause significant functional or aesthetic disadvantage. Understanding of the mechanisms of wound healing is pivotal for developing new therapies to prevent fibrotic scarring of large skin wounds caused by burns or other traumas.Tiivistelmä Ihohaavan nopea paraneminen on yksilön selviytymisen kannalta ratkaisevaa ihon elintärkeän suojaustehtävän vuoksi. Haavan paranemiseen liittyy useita kudosta korjaavia biologisia vasteita kuten hemostaasi, tulehdus, erilaisten solujen migraatio haava-alueelle, niiden jakautuminen ja erilaistuminen, angiogeneesi sekä sidekudoksen muodostus ja muokkaus. Häiriöt näissä tapahtumissa johtavat haavan kroonistumiseen tai liiallisen arpikudoksen muodostumiseen. Tarkastelemme akuutin haavan paranemisen vaiheita sekä arpeutumisen häiriöitä eli hypertrofisia arpia ja keloideja, jotka voivat aiheuttaa merkittävää toiminnallista ja kosmeettista haittaa. Haavan paranemiseen ja arven muodostumiseen liittyvien solu- ja molekyylitason mekanismien ymmärtäminen on ensiarvoisen tärkeää kehiteltäessä uusia hoitomenetelmiä palovammoista tai muista traumoista johtuvien laajojen ihoalueiden arpeutumisen ehkäisemiseen.Summary Wound healing and pathological scarring Efficient healing of skin wounds is crucial because of the vital barrier function of the skin. Multiple tightly coordinated regenerative responses are involved in the healing process, including hemostasis, migration of various cell types into the wound, inflammation, angiogenesis, and formation of the extracellular matrix. This review summarizes the phases of acute wound healing and excessive scarring which can lead to formation of hypertrophic scars or keloids, the two types of fibrotic scars that can cause significant functional or aesthetic disadvantage. Understanding of the mechanisms of wound healing is pivotal for developing new therapies to prevent fibrotic scarring of large skin wounds caused by burns or other traumas

Haavan paraneminen - diabetes sekä muut esteet ja hidasteet

Krooniset haavat ja haavan paranemisen pitkittyminen ovat merkittäviä kliinisiä ongelmia. Haavan paraneminen on monimutkainen biologinen prosessi, joka voidaan jakaa neljään vaiheeseen: verenvuodon tyrehtymiseen sekä sitä seuraaviin tulehdus-, korjaus- ja kypsymisvaiheisiin, joita säätelevät paikalliset olosuhteet. Haavan paranemiseen vaikuttaa myös yksilön yleistila kaikkine sairauksineen ja lääkityksineen. Paikallisista tekijöistä muun muassa tulehdusreaktiovaiheen pitkittyminen ja huono verenkierto edistävät haavojen kroonistumista. Diabetekseen liittyy huonontunut haavojen paranemistaipumus. Hyperglykemia heikentää haavan paranemista useilla eri mekanismeilla, joista yksi keskeinen perustuu hyperglykemian seurauksena kudoksiin ylimäärin kertyneiden, ei-entsymaattisesti liikaglykosyloituneiden molekyylien (advanced glycosylation end-products, AGE) käynnistämiin solubiologisiin häiriöihin. Paras keino estää hyperglykemian haitallinen vaikutus on tavoitella suositusten mukaista verenglukoosipitoisuutta

Contribution of collagen XIII to lung function and development of pulmonary fibrosis

Abstract Background: Collagen XIII is a transmembrane collagen associated with neuromuscular junction development, and in humans its deficiency results in congenital myasthenic syndrome type 19 (CMS19), which leads to breathing difficulties. CMS19 patients usually have restricted lung capacity and one patient developed chronic lung disease. In single-cell RNA sequencing studies, collagen XIII has been identified as a marker for pulmonary lipofibroblasts, which have been implicated in the resolution of pulmonary fibrosis. Methods: We investigated the location and function of collagen XIII in the lung to understand the origin of pulmonary symptoms in human CMS19 patients. Additionally, we performed immunostainings on idiopathic pulmonary fibrosis (IPF) samples (N=5) and both normal and fibrotic mouse lung. To study whether the lack of collagen XIII predisposes to restrictive lung disease, we exposed Col13a1-modified mice to bleomycin-induced pulmonary fibrosis. Results: Apparently normal alveolar septum sections of IPF patients′ lungs stained faintly for collagen XIII, and its expression was pinpointed to the septal fibroblasts in the mouse lung. Lung capacity was increased in mice lacking collagen XIII by over 10%. In IPF samples, collagen XIII was expressed by basal epithelial cells, hyperplastic alveolar epithelial cells and stromal cells in fibrotic areas, but the development of pulmonary fibrosis was unaffected in collagen XIII-deficient mice. Conclusions: Changes in mouse lung function appear to represent a myasthenic manifestation of collagen XIII deficiency. We suggest that respiratory muscle myasthenia is the primary cause of the breathing problems suffered by CMS19 patients in addition to skeletal deformities. Induction of collagen XIII expression in the IPF patients′ lungs warrants further studies to reveal collagen XIII-dependent disease mechanisms.Abstract Background: Collagen XIII is a transmembrane collagen associated with neuromuscular junction development, and in humans its deficiency results in congenital myasthenic syndrome type 19 (CMS19), which leads to breathing difficulties. CMS19 patients usually have restricted lung capacity and one patient developed chronic lung disease. In single-cell RNA sequencing studies, collagen XIII has been identified as a marker for pulmonary lipofibroblasts, which have been implicated in the resolution of pulmonary fibrosis. Methods: We investigated the location and function of collagen XIII in the lung to understand the origin of pulmonary symptoms in human CMS19 patients. Additionally, we performed immunostainings on idiopathic pulmonary fibrosis (IPF) samples (N=5) and both normal and fibrotic mouse lung. To study whether the lack of collagen XIII predisposes to restrictive lung disease, we exposed Col13a1-modified mice to bleomycin-induced pulmonary fibrosis. Results: Apparently normal alveolar septum sections of IPF patients′ lungs stained faintly for collagen XIII, and its expression was pinpointed to the septal fibroblasts in the mouse lung. Lung capacity was increased in mice lacking collagen XIII by over 10%. In IPF samples, collagen XIII was expressed by basal epithelial cells, hyperplastic alveolar epithelial cells and stromal cells in fibrotic areas, but the development of pulmonary fibrosis was unaffected in collagen XIII-deficient mice. Conclusions: Changes in mouse lung function appear to represent a myasthenic manifestation of collagen XIII deficiency. We suggest that respiratory muscle myasthenia is the primary cause of the breathing problems suffered by CMS19 patients in addition to skeletal deformities. Induction of collagen XIII expression in the IPF patients′ lungs warrants further studies to reveal collagen XIII-dependent disease mechanisms