Pilot screening of potential matrikines resulting from collagen breakages through ionizing radiation.

Little is known regarding radiation-induced matrikines and the possible degradation of extracellular matrix following therapeutic irradiation. The goal of this study was to determine if irradiation can cut collagen proteins at specific sites, inducing potentially biologically active peptides against cartilage cells. Chondrocytes cultured as 3D models were evaluated for extracellular matrix production. Bystander molecules were analyzed in vitro in the conditioned medium of X-irradiated chondrocytes. Preferential breakage sites were analyzed in collagen polypeptide by mass spectrometry and resulting peptides were tested against chondrocytes. 3D models of chondrocytes displayed a light extracellular matrix able to maintain the structure. Irradiated and bystander chondrocytes showed a surprising radiation sensitivity at low doses, characteristic of the presence of bystander factors, particularly following 0.1 Gy. The glycine-proline peptidic bond was observed as a preferential cleavage site and a possible weakness of the collagen polypeptide after irradiation. From the 46 collagen peptides analyzed against chondrocytes culture, 20 peptides induced a reduction of viability and 5 peptides induced an increase of viability at the highest concentration between 0.1 and 1 µg/ml. We conclude that irradiation promoted a site-specific degradation of collagen. The potentially resulting peptides induce negative or positive regulations of chondrocyte growth. Taken together, these results suggest that ionizing radiation causes a degradation of cartilage proteins, leading to a functional unbalance of cartilage homeostasis after exposure, contributing to cartilage dysfunction.

Pentastatin, a matrikine of the collagen IVα5, is a novel endogenous mediator of pulmonary endothelial dysfunction.

Deposition of basement membrane components, such as collagen IVα5, is associated with altered endothelial cell function in pulmonary hypertension. Collagen IVα5 harbors a functionally active fragment within its C-terminal noncollageneous (NC1) domain, called pentastatin, whose role in pulmonary endothelial cell behavior remains unknown. Here, we demonstrate that pentastatin serves as a mediator of pulmonary endothelial cell dysfunction, contributing to pulmonary hypertension. In vitro, treatment with pentastatin induced transcription of immediate early genes and proinflammatory cytokines and led to a functional loss of endothelial barrier integrity in pulmonary arterial endothelial cells. Mechanistically, pentastatin leads to ß1-integrin subunit clustering and Rho/ROCK activation. Blockage of the ß1-integrin subunit or the Rho/ROCK pathway partially attenuated the pentastatin-induced endothelial barrier disruption. Although pentastatin reduced the viability of endothelial cells, smooth muscle cell proliferation was induced. These effects on the pulmonary vascular cells were recapitulated ex vivo in the isolated-perfused lung model, where treatment with pentastatin-induced swelling of the endothelium accompanied by occasional endothelial cell apoptosis. This was reflected by increased vascular permeability and elevated pulmonary arterial pressure induced by pentastatin. This study identifies pentastatin as a mediator of endothelial cell dysfunction, which thus might contribute to the pathogenesis of pulmonary vascular disorders such as pulmonary hypertension.NEW & NOTEWORTHY This study is the first to show that pentastatin, the matrikine of the basement membrane (BM) collagen IVα5 polypeptide, triggers rapid pulmonary arterial endothelial cell barrier disruption, activation, and apoptosis in vitro and ex vivo. Mechanistically, pentastatin partially acts through binding to the ß1-integrin subunit and the Rho/ROCK pathway. These findings are the first to link pentastatin to pulmonary endothelial dysfunction and, thus, suggest a major role for BM-matrikines in pulmonary vascular diseases such as pulmonary hypertension.

Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib-resistant NF-κB activity and increases drug resistance in multiple myeloma.

Nuclear factor-κB (NF-κB) is a family of transcription factors that play a key role in cell survival and proliferation in many hematological malignancies, including multiple myeloma (MM). Bortezomib, a proteasome inhibitor used in the management of MM, can inhibit both canonical and noncanonical activation of NF-κB in MM cells. However, we previously reported that a significant fraction of freshly isolated MM cells harbor bortezomib-resistant NF-κB activity. Here, we report that hyaluronan and proteoglycan link protein 1 (HAPLN1) is produced in bone marrow stromal cells from MM patients, is detected in patients' bone marrow plasma, and can activate an atypical bortezomib-resistant NF-κB pathway in MM cells. We found that this pathway involves bortezomib-resistant degradation of the inhibitor of NF-κB (IκBα), despite efficient bortezomib-mediated inhibition of proteasome activity. Moreover, HAPLN1 can also confer bortezomib-resistant survival of MM cells. We propose that HAPLN1 is a novel pathogenic factor in MM that induces an atypical NF-κB activation and thereby promotes bortezomib resistance in MM cells.

The matrikine acetyl-proline-glycine-proline and clinical features of COPD: findings from SPIROMICS.

BACKGROUND: Pulmonary and systemic inflammation are central features of chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated relationships between biologically active extracellular matrix components, or matrikines, and COPD pathogenesis. We studied the relationships between the matrikine acetyl-proline-glycine-proline (AcPGP) in sputum and plasma and clinical features of COPD. METHODS: Sputum and plasma samples were obtained from COPD participants in the SPIROMICS cohort at enrollment. AcPGP was isolated using solid phase extraction and measured by mass spectrometry. Demographics, spirometry, quality of life questionnaires, and quantitative computed tomography (CT) imaging with parametric response mapping (PRM) were obtained at baseline. Severe COPD exacerbations were recorded at 1-year of prospective follow-up. We used linear and logistic regression models to measure associations between AcPGP and features of COPD, and Kaplan-Meier analyses to measure time-to-first severe exacerbation. RESULTS: The 182 COPD participants in the analysis were 66 ± 8 years old, 62% male, 84% White race, and 39% were current smokers. AcPGP concentrations were 0.61 ± 1.89 ng/mL (mean ± SD) in sputum and 0.60 ± 1.13 ng/mL in plasma. In adjusted linear regression models, sputum AcPGP was associated with FEV1/FVC, spirometric GOLD stage, PRM-small airways disease, and PRM-emphysema. Sputum AcPGP also correlated with severe AECOPD, and elevated sputum AcPGP was associated with shorter time-to-first severe COPD exacerbation. In contrast, plasma AcPGP was not associated with symptoms, pulmonary function, or severe exacerbation risk. CONCLUSIONS: In COPD, sputum but not plasma AcPGP concentrations are associated with the severity of airflow limitation, small airways disease, emphysema, and risk for severe AECOPD at 1-year of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS).

The matrikine N-acetylated proline-glycine-proline induces premature senescence of nucleus pulposus cells via CXCR1-dependent ROS accumulation and DNA damage and reinforces the destructive effect of these cells on homeostasis of intervertebral discs.

Intervertebral disc (IVD) cell senescence is a recognized mechanism of intervertebral disc degeneration (IDD). Elucidating the molecular mechanisms underlying disc cell senescence will contribute to understanding the pathogenesis of IDD. We previously reported that N-acetylated proline-glycine-proline (N-Ac-PGP), a matrikine, is involved in the process of IDD. However, its roles in IDD are not well understood. Here, using rat nucleus pulposus (NP) cells, we found that N-Ac-PGP induced premature senescence of NP cells by binding to CXCR1. N-Ac-PGP induced DNA damage and reactive oxygen species accumulation in NP cells, which resulted in activation of the p53-p21-Rb and p16-Rb pathways. Moreover, the RT2 profiler PCR array showed that N-Ac-PGP down-regulates the expression of antioxidant genes in NP cells, suggesting a decline in the antioxidants of NP cells. On the other hand, N-Ac-PGP up-regulated the expression of matrix catabolic genes and inflammatory genes in NP cells. Concomitantly, N-Ac-PGP reinforced the destructive effects of senescent NP cells on the homeostasis of the IVDs in vivo. Our study suggests that N-Ac-PGP plays critical roles in the pathogenesis of IDD through the induction of premature senescence of disc cells and via the activation of catabolic and inflammatory cascades in disc cells. N-Ac-PGP also deteriorates the redox environment of disc cells. Hence, N-Ac-PGP is a new potential therapeutic target for IDD.

Adapting extracellular matrix proteomics for clinical studies on cardiac remodeling post-myocardial infarction.

Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve stimulation of robust inflammation to clear necrotic myocytes and tissue debris and induction of extracellular matrix (ECM) protein synthesis to generate a scar. Proteomic strategies provide us with a means to index the ECM proteins expressed in the LV, quantify amounts, determine functions, and explore interactions. This review will focus on the efforts taken in the proteomics research field that have expanded our understanding of post-MI LV remodeling, concentrating on the strengths and limitations of different proteomic approaches to glean information that is specific to ECM turnover in the post-MI setting. We will discuss how recent advances in sample preparation and labeling protocols increase our successes at detecting components of the cardiac ECM proteome. We will summarize how proteomic approaches, focusing on the ECM compartment, have progressed over time to current gel-free methods using decellularized fractions or labeling strategies that will be useful for clinical applications. This review will provide an overview of how cardiac ECM proteomics has evolved over the last decade and will provide insight into future directions that will drive forward our understanding of cardiac ECM turnover in the post-MI LV.

Matrikines from basement membrane collagens: a new anti-cancer strategy.

BACKGROUND: Tumor microenvironment is a complex system composed of a largely altered extracellular matrix with different cell types that determine angiogenic responses and tumor progression. Upon the influence of hypoxia, tumor cells secrete cytokines that activate stromal cells to produce proteases and angiogenic factors. In addition to stromal ECM breakdown, proteases exert various pro- or anti-tumorigenic functions and participate in the release of various ECM fragments, named matrikines or matricryptins, capable to act as endogenous angiogenesis inhibitors and to limit tumor progression. SCOPE OF REVIEW: We will focus on the matrikines derived from the NC1 domains of the different constitutive chains of basement membrane-associated collagens and mainly collagen IV. MAJOR CONCLUSIONS: The putative targets of the matrikine control are the proliferation and invasive properties of tumor or inflammatory cells, and the angiogenic and lymphangiogenic responses. Collagen-derived matrikines such as canstatin, tumstatin or tetrastatin for example, decrease tumor growth in various cancer models. Their anti-cancer activities comprise anti-proliferative effects on tumor or endothelial cells by induction of apoptosis or cell cycle blockade and the induction of a loss of their migratory phenotype. They were used in various preclinical therapeutic strategies: i) induction of their overexpression by cancer cells or by the host cells, ii) use of recombinant proteins or synthetic peptides or structural analogues designed from the structure of the active sequences, iii) used in combined therapies with conventional chemotherapy or radiotherapy. GENERAL SIGNIFICANCE: Collagen-derived matrikines strongly inhibited tumor growth in many preclinical cancer models in mouse. They constitute a new family of anti-cancer agents able to limit cancer progression. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Proteolytic modulation of tumor microenvironment signals during cancer progression.

Under normal conditions, the cellular microenvironment is optimized for the proper functioning of the tissues and organs. Cells recognize and communicate with the surrounding cells and extracellular matrix to maintain homeostasis. When cancer arises, the cellular microenvironment is modified to optimize its malignant growth, evading the host immune system and finding ways to invade and metastasize to other organs. One means is a proteolytic modification of the microenvironment and the signaling molecules. It is now well accepted that cancer progression relies on not only the performance of cancer cells but also the surrounding microenvironment. This mini-review discusses the current understanding of the proteolytic modification of the microenvironment signals during cancer progression.

F4, a collagen XIX-derived peptide, inhibits tumor angiogenesis through αvß3 and α5ß1 integrin interaction.

We previously demonstrated that F4 peptide (CNPEDCLYPVSHAHQR) from collagen XIX was able to inhibit melanoma cell migrationin vitro and cancer progression in a mouse melanoma model. The aim of the present work was to study the anti-angiogenic properties of F4 peptide. We demonstrated that F4 peptide inhibited VEGF-induced pseudo-tube formation on Matrigel by endothelial cells and endothelial sprouting in a rat aortic ring assay. By affinity chromatography, we identified αvß3 and α5ß1 integrins as potential receptors for F4 peptide on endothelial cell surface. Using solid phase assays, we proved the direct interaction between F4 and both integrins. Taken together, our results demonstrate that F4 peptide is a potent antitumor agent inhibiting both angiogenesis and tumor cell migration.

Cartilage Oligomeric Matrix Protein-Derived Peptides Secreted by Cartilage Do Not Induce Responses Commonly Observed during Osteoarthritis.

OBJECTIVE: To evaluate if 3 peptides derived from the cartilage oligomeric matrix protein (COMP), which wounded zones of cartilage secrete into synovial fluid, possess biological activity and might therefore be involved in the regulation of specific aspects of joint regeneration. METHODS: The 3 peptides were produced by chemical synthesis and then tested in vitro for known functions of the COMP C-terminal domain from which they derive, and which are involved in osteoarthritis: transforming growth factor-ß (TGF-ß) signaling, vascular homeostasis, and inflammation. Results. None of the peptides affected the gene expression of COMP in osteochondral progenitor cells (P > 0.05). We observed no effects on the vascularization potential of endothelial cells (P > 0.05). In cultured synovium explants, no differences on the expression of catabolic enzymes or proinflammatory cytokines were found when peptides were added (P > 0.05). DISCUSSION AND CONCLUSIONS: The 3 peptides tested do not regulate TGF-ß signaling, angiogenesis and vascular tube formation, or synovial inflammation in vitro and therefore most likely do not play a major role in the disease process.

Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis.

BACKGROUND: Proline-glycine-proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms. METHODS: Broncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed. RESULTS: Whilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase. CONCLUSIONS: A striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.

Versican: A Dynamic Regulator of the Extracellular Matrix.

Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan belonging to the aggrecan/lectican family. In adults, this proteoglycan serves as a structural macromolecule of the extracellular matrix in the brain and large blood vessels. In contrast, versican is transiently expressed at high levels during development and under pathological conditions when the extracellular matrix dramatically changes, including in the inflammation and repair process. There are many reports showing the upregulation of versican in cancer, which correlates with cancer aggressiveness. Versican has four classical splice variants, and all the variants contain G1 and G3 domains at N- and C-termini, respectively. There are two glycosaminoglycan attachment domains CSα and CSß. The largest V0 variant contains both CSα and CSß, V1 contains CSß, V2 contains CSα, and the shortest G3 variant has neither of them. Versican degradation is initiated by cleavage at a site in the CSß domain by ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases. The N-terminal fragment containing the G1 domain has been reported to exert various biological functions, although its mechanisms of action have not yet been elucidated. In this review, we describe the role of versican in inflammation and cancer and also address the biological function of versikine.

Angiogenesis Inhibition by a Short 13 Amino Acid Peptide Sequence of Tetrastatin, the α4(IV) NC1 Domain of Collagen IV.

Angiogenesis is defined as the formation of new capillaries by sprouting from the pre-existing microvasculature. It occurs in physiological and pathological processes particularly in tumor growth and metastasis. α1, α2, α3, and α6 NC1 domains from type IV collagen were reported to inhibit tumor angiogenesis. We previously demonstrated that the α4 NC1 domain from type IV collagen, named Tetrastatin, inhibited tumor growth in a mouse melanoma model. The inhibitory activity was located in a 13 amino acid sequence named QS-13. In the present paper, we demonstrate that QS-13 decreases VEGF-induced-angiogenesis in vivo using the Matrigel plug model. Fluorescence molecular tomography allows the measurement of a 65% decrease in Matrigel plug angiogenesis following QS-13 administration. The results are confirmed by CD31 microvessel density analysis on Matrigel plug slices. QS-13 peptide decreases Human Umbilical Vein Endothelial Cells (HUVEC) migration and pseudotube formation in vitro. Relevant QS-13 conformations were obtained from molecular dynamics simulations and docking. A putative interaction of QS-13 with α5ß1 integrin was investigated. The interaction was confirmed by affinity chromatography, solid phase assay, and surface plasmon resonance. QS-13 binding site on α5ß1 integrin is located in close vicinity to the RGD binding site, as demonstrated by competition assays. Collectively, our results suggest that QS-13 exhibits a mighty anti-angiogenic activity that could be used in cancer treatment and other pathologies with excessive angiogenesis such as hemangioma, psoriasis or diabetes.

Vastatin (the NC1 domain of human type VIII collagen a1 chain) is linked to stromal reactivity and elevated in serum from patients with colorectal cancer.

Vastatin, a fragment derived from type VIII collagen, is one of the least studied collagen-derived matrikines. Vastatin can be detected in serum but little is known regarding the relevance of serum vastatin in colorectal cancer (CRC). In this study, serum vastatin was measured (ELISA) in 67 healthy controls and 48 CRC patients prior to resection and compared to clinicopathological parameters and serum biomarkers of stromal reactivity (C3M, VICM). Impact of resection and chemotherapy were evaluated by comparing baseline values with a 3-month follow-up sample (n = 23). Serum vastatin was detectable in 114 of 115 subjects. At baseline vastatin was elevated in CRC compared to controls (P < 0.001) with a diagnostic accuracy (AUROC) of 0.865, p < 0.0001. Vastatin correlated with age in controls but not in patients with CRC; no association was seen with clinicopathological parameters. Vastatin was independently associated with C3M (stepwise linear regression coefficient 0.25, p = 0.046). Overall, no difference was seen in vastatin levels between baseline and follow-up. In conclusion, vastatin is elevated in serum from patients with CRC and correlate with interstitial matrix degradation (C3M). This indicates that vastatin is linked to stromal reactivity and suggests that vastatin has biomarker potential in CRC. The association with clinicopathological parameters and treatment effect needs further evaluation.

What is the role of peptide fragments of collagen I and IV in health and disease?

Collagen is the most abundant protein in mammalian systems; it can be found in organs such as bones, the liver, kidney, heart, teeth, and skin. Collagen provides the necessary structural framework for tissues in which it is found. However, if there are any alterations in the delicate balance of collagen types in the extracellular matrix (ECM), then problems arise. For example, increasing collagen I:III ratio would provide additional rigidity to tissue structure, whereas decreasing this ratio would provide elasticity and flexibility to the tissue. The proper function of tissues is reliant on this scale not tipping too far in either direction. Major players in the process of ECM remodeling, both normal and adverse, are the fibroblast cells via the secretion of collagen precursors and matrix metalloproteinases, with the latter responsible for ECM degradation. The collagen peptides created by the proteolytic cleavage of these collagen fibrils, while once thought to have an absence of function, have been shown over recent years to potentiate and regulate a variety of cellular processes acting through integrin receptors. Many collagen peptides have been identified from many different collagen types and have been shown to regulate processes such as cell proliferation, migration, apoptosis, and reduce angiogenesis. The collagen peptides of interest are those generated from the primary collagen type of tissue interstitial matrix, collagen type I, and the basement membrane, collagen type IV. Thus, this review looks to highlight some examples of unorthodox functional roles of collagen and its peptides in regulating physiological health and disease.

Inflammation-Generated Extracellular Matrix Fragments Drive Lung Metastasis.

Mechanisms explaining the propensity of a primary tumor to metastasize to a specific site still need to be unveiled, and clinical studies support a link between chronic inflammation and cancer dissemination to specific tissues. Using different mouse models, we demonstrate the role of inflammation-generated extracellular matrix fragments ac-PGP (N-acetyl-proline-glycine-proline) on tumor cells dissemination to lung parenchyma. In mice exposed to cigarette smoke or lipopolysaccharide, lung neutrophilic inflammation produces increased levels of MMP-9 (matrix metalloproteinase 9) that contributes to collagen breakdown and allows the release of ac-PGP tripeptides. By silencing CXCR2 gene expression in tumor cells, we show that these generated ac-PGP tripeptides exert a chemotactic activity on tumor cells in vivo by binding CXCR2.

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5ß1 integrin.

The haematopoietic niche is contributed to by bone marrow-resident mesenchymal stromal cells (BM-MSCs) and subverted by prostate cancer cells. To study mechanisms by which BM-MSCs and prostate cancer cells may interact, we assessed the migration, invasion, adhesion and proliferation of bone-derived prostate cancer cells (PC-3) in co-culture with pluripotent human BM-MSCs. We observed a strong adhesive, migratory and invasive phenotype of PC-3 cells with BM- MSC-co-culture and set out to isolate and characterize the bioactive principle. Initial studies indicated that chemotaxis was secondary to a protein residing in the >100kDa fraction. Size-exclusion chromatography (SEC) recovered peak activity in a high-molecular weight fraction containing thrombospondin-1 (TSP1). While TSP1 immunodepletion decreased activity, put-back with purified TSP1 did not reproduce bioactivity. Further purification of the TSP1-containing high-molecular weight fraction of the BM-MSC secretome with heparin-affinity chromatography recovered bioactivity with highly restricted bands on polyacrylamide gel electrophoresis, determined by mass spectroscopy to be proteolytic fragments of fibronectin (FN). Put-back experiments with full-length FN permitted adhesion but failed to induce migration. Monospecific antibodies to FN blocked adhesion. Proteolytic cleavage of FN generated FN fragments which now induced migration. Neutralizing monoclonal antibodies to FN receptors α5 and ß1 integrins, and α5 knockdown specifically blocked migration and adhesion. CONCLUSION: Fibronectin fragments (FNFr) function as matrikines driving the chemotactic affinity of prostate cancer cells via the α5ß1 integrin. Taken together with the high-frequency of α5ß1 expression in disseminated prostate cancer cells in bone marrow aspirates from patients, the FNFr/FN-α5ß1 interaction warrants further study as a therapeutic target.

Type XIX collagen: A new partner in the interactions between tumor cells and their microenvironment.

Type XIX collagen is a minor collagen that is associated with the basement membrane zone that belongs to the FACIT family (Fibril-Associated Collagens with Interrupted Triple helices). The FACIT family is composed of type IX, XII, XIV, XVI, XX, XXI, XXII and XIX collagens, which share many highly conserved structural motifs: a short NC1 domain, a thrombospondin-like N-terminal domain (TSPN), and numerous cysteine residues. The main role of FACITs is to ensure the integrity and stability of the extracellular matrix and its fibrillar collagen network by regulating the formation and size of the collagen fibrils. Type XIX collagen was discovered in a human rhabdomyosarcoma cell line. The collagen α1(XIX) chain is composed of 5 triple-helical domains (COL) interrupted by 6 non-triple-helical (NC) domains with a short, C-terminal, 19 amino acid non-collagenous domain (NC1). This collagen is involved in the differentiation of muscle cells, central nervous system development, and formation of the esophagus. Type XIX collagen is associated with the basement membrane zone, like type XVIII and XV collagens. Its short NC1(XIX) C-terminal domain inhibits the migration and invasion of melanoma cells. It also exerts a strong anti-angiogenic effect by inhibiting MMP-14 and VEGF expression. NC1(XIX) binding to αvß3 integrin decreases the phosphorylation of proteins involved in the FAK (Focal Adhesion Kinase)/PI3K (PhosphoInositide 3-Kinase)/Akt (protein kinase B)/mTOR (Mammalian Target Of Rapamycin) pathway. On the other hand, NC1(XIX) induces an increase in GSK3ß activity by decreasing its level of phosphorylation. The inhibition of this pathway could explain the anti-tumor properties of the NC1(XIX) domain.

Skin rejuvenation using cosmetic products containing growth factors, cytokines, and matrikines: a review of the literature.

Skin aging is primarily due to alterations in the dermal extracellular matrix, especially a decrease in collagen I content, fragmentation of collagen fibrils, and accumulation of amorphous elastin material, also known as elastosis. Growth factors and cytokines are included in several cosmetic products intended for skin rejuvenation because of their ability to promote collagen synthesis. Matrikines and matrikine-like peptides offer the advantage of growth factor-like activities but better skin penetration due to their much smaller molecular size. In this review, we summarize the commercially available products containing growth factors, cytokines, and matrikines for which there is evidence that they promote skin rejuvenation.

Skin tissue repair: Matrix microenvironmental influences.

The process of repair of wounded skin involves intricate orchestration not only between the epidermal and dermal compartments but also between the resident and immigrant cells and the local microenvironment. Only now are we beginning to appreciate the complex roles played by the matrix in directing the outcome of the repair processes, and how this impacts the signals from the various cells. Recent findings speak of dynamic and reciprocal interactions that occurs among the matrix, growth factors, and cells that underlies this integrated process. Further confounding this integration are the physiologic and pathologic situations that directly alter the matrix to impart at least part of the dysrepair that occurs. These topics will be discussed with a call for innovative model systems of direct relevance to the human situation.