Tumor- and Osteoblast-Derived Periostin in Prostate Cancer bone Metastases

Exploring the biological function of periostin (POSTN) in prostate cancer (PCa) bone metastasis is of importance. It was observed that the expression of POSTN was high in PCa, especially highest in PCa metastasized to bone. In this study, we found that inhibiting POSTN in PCa cells could significantly alleviate PCa bone metastasis in vivo, suggesting POSTN is a promising therapeutic target. Since, due to the secreted expression of POSTN in osteoblasts and PCa, we hypothesized the positive feedback loop between osteoblasts and PCa mediated by POSTN in PCa bone metastasis. The in vitro experiments demonstrated that osteoblast-derived POSTN promoted PCa cell proliferation and invasion and PCa cell-derived POSTN promotes proliferation of osteoblasts. Furthermore, we found that POSTN regulated PCa and osteoblast function through integrin receptors. Finally, 18F-Alfatide II was used as the molecule probe of integrin αvβ3 in PET-CT, revealing high intake in metastatic lesions. Our findings together indicate that targeting POSTN in PCa cells as well as in the osteoblastic may be an effective treatment for PCa bone metastasis.

OPN Inhibits Autophagy through CD44, Integrin and the MAPK Pathway in Osteoarthritic Chondrocytes

Background: To investigate whether OPN has an effect on autophagy in human osteoarthritic chondrocytes and determine the roles of CD44, αvβ3 integrin and the MAPK pathway in this progress. Methods: First, we cultured human OA chondrocytes in vitro and then treated cells with rhOPN to determine autophagy changes. Next , the anti-CD44 and anti-CD51/61 monoclonal antibodies (Abs) or isotype IgG were used to determine the possible role of CD44 and αvβ3 integrin; subsequently, an inhibitor of the ERK MAPK pathway was used to investigate the role of ERK MAPK. Western blotting was used to measure the beclin1, LC3 II and MAPK protein expression, and mRFP-GFP-LC3 confocal imaging was used to detect the autophagy levels. CCK-8 was used to assay the proliferation and activity of chondrocytes. Results: Our results showed that the LC3 protein was greatly decreased in OA cartilage compared to normal cartilage ,and OPN suppressed the autophagy activity in chondrocytes in vitro. Blocking experiments with anti-CD44 and anti-CD51/61 Abs indicated that OPN could suppress the expression of LC3II and beclin1 through αvβ3 integrin and CD44. Our results also indicated that the ratio of p-ERK/ ERK but not p-P38/P38 and p-JNK/JNK was increased after the rhOPN treatment. The ERK inhibitor inhibited the activity of OPN in the suppression of autophagy, and the CCK-8 results showed that rhOPN could promote chondrocyte proliferation. Conclusions: OPN inhibited chondrocyte autophagy through CD44 and αvβ3 integrin receptors and via the ERK MAPK signaling pathway.

Function and Mechanism of RGD in Bone and Cartilage Tissue Engineering

Bone and cartilage injury is common, tissue engineered scaffolds are potential means to repair. Because most of the scaffold materials used in bone and cartilage tissue engineering are bio-inert, it is necessary to increase the cellular adhesion ability of during tissue engineering reconstruction. The Arginine - Glycine - Aspartic acid (Arg-Gly-Asp, RGD) peptide family is considered as a specific recognition site for the integrin receptors. Integrin receptors are key regulators of cell-cell and cell-extracellular microenvironment communication. Therefore, the RGD polypeptide families are considered as suitable candidates for treatment of a variety of diseases and for the regeneration of various tissues and organs. Many scaffold material for tissue engineering and has been approved by US Food and Drug Administration (FDA) for human using. The application of RGD peptides in bone and cartilage tissue engineering was reported seldom. Only a few reviews have summarized the applications of RGD peptide with alloy, bone cements, and PCL in bone tissue engineering. Herein, we summarize the application progress of RGD in bone and cartilage tissue engineering, discuss the effects of structure, sequence, concentration, mechanical stimulation, physicochemical stimulation, and time stimulation of RGD peptide on cells differentiation, and introduce the mechanism of RGD peptide through integrin in the field of bone and cartilage tissue engineering.

Cell-extracellular matrix dynamics

The sites of interaction between a cell and its surrounding microenvironment serve as dynamic signaling hubs that regulate cellular adaptations during developmental processes, immune functions, wound healing, cell migration, cancer invasion and metastasis, as well as in many other disease states. For most cell types, these interactions are established by integrin receptors binding directly to extracellular matrix proteins, such as the numerous collagens or fibronectin. For the cell, these points of contact provide vital cues by sampling environmental conditions, both chemical and physical. The overall regulation of this dynamic interaction involves both extracellular and intracellular components and can be highly variable. In this review, we highlight recent advances and hypotheses about the mechanisms and regulation of cell-ECM interactions, from the molecular to the tissue level, with a particular focus on cell migration. We then explore how cancer cell invasion and metastasis are deeply rooted in altered regulation of this vital interaction.

Omentin-1 Modulates Macrophage Function via Integrin Receptors αvβ3 and αvβ5 and Reverses Plaque Vulnerability in Animal Models of Atherosclerosis

Backgrounds: Omentin-1 is a novel cytokine that is primarily released by the epicardial adipose tissue. Molecular structure analysis revealed that it contained a fibrinogen-like domain. Clinical studies have demonstrated that the expression of omentin-1 is tightly associated with the development of cardiovascular diseases, but the receptor by which omentin-1 modulates macrophage function has not been identified yet.Objective: This study sought to investigate the effect of omentin-1 on already-established atherosclerosis (AS) lesions in both ApoE−/− and Ldlr−/− mice and further, study its underlying mechanisms.Methods and Results: We investigated the effect of omentin-1 on the plaque phenotype by implanting a minipump in ApoE−/− and Ldlr−/− mice. In vivo studies showed that the infusion of omentin-1 increased the collagen content and mitigated the formation of the necrotic core in both animal models. Immunohistochemistry and immunofluorescence analysis revealed that omentin-1 suppressed inflammatory cytokines expression, macrophage infiltration, and apoptosis within the plaque. An immunoprecipitation experiment and confocal microscopy analysis confirmed the binding of omentin-1 to the integrin receptors αvβ3 and αvβ5. The cell studies demonstrated that omentin-1 suppressed the apoptosis and inflammatory cytokines expression induced by the oxidized low-density lipoprotein in the macrophage. In addition, omentin-1 promoted the phosphorylation of the integrin-relevant signaling pathway as well as the Akt and AMPK in the macrophage. The addition of the inhibitor of the integrin receptor or interfering with the expression of the integrin subunit αv (ITGAV) both significantly abrogated the bioeffects induced by omentin-1. A flow cytometry analysis indicated that the antibodies against αvβ3 and αvβ5 had a competitive effect on the omentin-1 binding to the cell membrane.Conclusions: The administration of adipokine omentin-1 can inhibit the necrotic cores formation and pro-inflammatory cytokines expression within the AS lesion. The mechanisms may include the suppression of apoptosis and pro-inflammatory cytokines expression in the macrophage by binding to the integrin receptors αvβ3 and αvβ5.

Role of Integrins in Sperm Activation and Fertilization

In mammals, integrins are heterodimeric transmembrane glycoproteins that represent a large group of cell adhesion receptors involved in cell–cell, cell–extracellular matrix, and cell–pathogen interactions. Integrin receptors are an important part of signalization pathways and have an ability to transmit signals into and out of cells and participate in cell activation. In addition to somatic cells, integrins have also been detected on germ cells and are known to play a crucial role in complex gamete-specific physiological events, resulting in sperm-oocyte fusion. The main aim of this review is to summarize the current knowledge on integrins in reproduction and deliver novel perspectives and graphical interpretations presenting integrin subunits localization and their dynamic relocation during sperm maturation in comparison to the oocyte. A significant part of this review is devoted to discussing the existing view of the role of integrins during sperm migration through the female reproductive tract; oviductal reservoir formation; sperm maturation processes ensuing capacitation and the acrosome reaction, and their direct and indirect involvement in gamete membrane adhesion and fusion leading to fertilization.

A cell–ECM mechanism for connecting the ipsilateral eye to the brain

Information about features in the visual world is parsed by circuits in the retina and is then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors expressed by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell–extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.

Cyclodextrin Polymers as Delivery Systems for Targeted Anti-Cancer Chemotherapy

In the few last years, nanosystems have emerged as a potential therapeutic approach to improve the efficacy and selectivity of many drugs. Cyclodextrins (CyDs) and their nanoparticles have been widely investigated as drug delivery systems. The covalent functionalization of CyD polymer nanoparticles with targeting molecules can improve the therapeutic potential of this family of nanosystems. In this study, we investigated cross-linked γ- and β-cyclodextrin polymers as carriers for doxorubicin (ox) and oxaliplatin (Oxa). We also functionalized γ-CyD polymer bearing COOH functionalities with arginine-glycine-aspartic or arginine moieties for targeting the integrin receptors of cancer cells. We tested the Dox and Oxa anti-proliferative activity in the presence of the precursor polymer with COOH functionalities and its derivatives in A549 (lung, carcinoma) and HepG2 (liver, carcinoma) cell lines. We found that CyD polymers can significantly improve the antiproliferative activity of Dox in HepG2 cell lines only, whereas the cytotoxic activity of Oxa resulted as enhanced in both cell lines. The peptide or amino acid functionalized CyD polymers, loaded with Dox, did not show any additional effect compared to the precursor polymer. Finally, studies of Dox uptake showed that the higher antiproliferative activity of complexes correlates with the higher accumulation of Dox inside the cells. The results show that CyD polymers could be used as carriers for repositioning classical anticancer drugs such as Dox or Oxa to increase their antitumor activity.

Mitochondria Tether to Focal Adhesions During Cell Migration and Regulate Their Size.

Focal Adhesions (FA) couple the actin cytoskeleton to the extracellular matrix through transmembrane integrin receptors. FA assembly and disassembly regulate cell migration by controlling substrate interaction and the generation of intracellular contractile forces. Here we show that FA interact with mitochondria. Mitochondria are highly dynamic organelles that are now emerging as regulators of mammalian cell motility. We find that mitochondria infiltrate the leading edge of NIH3T3 fibroblasts during migration and tether to FA there. Importantly, we find that FA interacting with mitochondria are larger than those lacking mitochondrial interaction. In addition, inhibition of mitochondrial ATP generation reduces FA size and artificial tethering of FA to mitochondria concomitantly increases their size. Taken together this suggests that mitochondrial interaction with FA is a functional part of cell migration and adhesion.

Integrins: An Important Link between Angiogenesis, Inflammation and Eye Diseases

Integrins belong to a group of cell adhesion molecules (CAMs) which is a large group of membrane-bound proteins. They are responsible for cell attachment to the extracellular matrix (ECM) and signal transduction from the ECM to the cells. Integrins take part in many other biological activities, such as extravasation, cell-to-cell adhesion, migration, cytokine activation and release, and act as receptors for some viruses, including severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). They play a pivotal role in cell proliferation, migration, apoptosis, tissue repair and are involved in the processes that are crucial to infection, inflammation and angiogenesis. Integrins have an important part in normal development and tissue homeostasis, and also in the development of pathological processes in the eye. This review presents the available evidence from human and animal research into integrin structure, classification, function and their role in inflammation, infection and angiogenesis in ocular diseases. Integrin receptors and ligands are clinically interesting and may be promising as new therapeutic targets in the treatment of some eye disorders.