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LOXL2 attenuates osteoarthritis through inactivating Integrin/FAK signaling.

ABSTRACT: Temporomandibular joint OA (TMJOA) is a common degenerative joint disease, leads to structural damage and ultimately loss of function. Matrix degradation is one of the first pathogenesis during the progression of OA, it was effective to inhibit matrix degradation to block the development of OA. In this study, an in vivo model (compressive mechanical force) and an in vitro model (IL-1β) were used to induce OA-like changes in TMJ cartilage and chondrocytes. We revealed lysyl oxidase like-2 (LOXL2) play a critical role in TMJOA. LOXL2 expression decreased in mechanical stress/IL-β induced TMJOA-like lesions in both in vivo models and in vitro models. Furthermore, recombinant LOXL2 (rhLOXL2) treatment ameliorated the degenerative changes induced by mechanical stress in vivo, including the thinning cartilage, down-expression of collagen II and proteoglycan, and over-expression of TNF-a, while LOXL2 antibody (anti-LOXL2) treatment exacerbated these changes. Mechanistically, the protection of LOXL2 in chondrocytes was induced partly through activation of the Integrin/FAK pathway. The inhibition of the Integrin/FAK pathway could neutralized the effects caused by rhLOXL2. Collectively, our study suggests that the LOXL2 plays a protective role in mechanical stress induced TMJOA-like changes, and the Integrin/FAK pathway may be a key downstream pathway in this process.

SUBMITTER: Zhang C

PROVIDER: S-EPMC8382747 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tumor-secreted LOXL2 activates fibroblasts through FAK signaling.

Project description:UNLABELLED:Cancer-associated fibroblasts enhance cancer progression when activated by tumor cells through mechanisms not yet fully understood. Blocking mammary tumor cell-derived lysyl oxidase-like 2 (LOXL2) significantly inhibited mammary tumor cell invasion and metastasis in transgenic and orthotopic mouse models. Here, we discovered that tumor-derived LOXL2 directly activated stromal fibroblasts in the tumor microenvironment. Genetic manipulation or antibody inhibition of LOXL2 in orthotopically grown mammary tumors reduced the expression of ?-smooth muscle actin (?-SMA). Using a marker for reticular fibroblasts, it was determined that expression of ?-SMA was localized to fibroblasts recruited from the host tissue. This marker also revealed that the matrix present in tumors with reduced levels of LOXL2 was more scattered compared with control tumors which exhibited matrices with dense, parallel alignments. Importantly, in vitro assays revealed that tumor-derived LOXL2 and a recombinant LOXL2 protein induced fibroblast branching on collagen matrices, as well as increased fibroblast-mediated collagen contraction and invasion of fibroblasts through extracellular matrix. Moreover, LOXL2 induced the expression of ?-SMA in fibroblasts grown on collagen matrices. Mechanistically, it was determined that LOXL2 activated fibroblasts through integrin-mediated focal adhesion kinase activation. These results indicate that inhibition of LOXL2 in tumors not only reduces tumor cell invasion but also attenuates the activation of host cells in the tumor microenvironment. IMPLICATIONS:These findings reveal new insight into the mechanisms of fibroblast activation, a novel function of LOXL2, and further highlight the importance of generating LOXL2-targeted therapies for the prevention of tumor progression and metastasis.

| S-EPMC3833835 | biostudies-literature

Kinsenoside attenuates osteoarthritis by repolarizing macrophages through inactivating NF-?B/MAPK signaling and protecting chondrocytes.

Project description:The objective was to investigate the effect of kinsenoside (Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis (OA) progression. RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium (CM) and IL-1? were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection (ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of I?B?, which further reduced the downstream phosphorylation of P65 in nuclear factor-?B (NF-?B) signaling. Moreover, Kin inhibited mitogen-activated protein kinases (MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1?-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages, promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.

| S-EPMC6804452 | biostudies-literature

IL-32γ attenuates airway fibrosis by modulating the integrin-FAK signaling pathway in fibroblasts.

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| S-EPMC6158920 | biostudies-literature

CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway.

Project description:Caveolin-1 (CAV1) is the main structural component of caveolae, which are plasma membrane invaginations that participate in vesicular trafficking and signal transduction events. Although evidence describing the function of CAV1 in several cancer types has recently accumulated, its role in melanoma tumor formation and progression remains poorly explored. Here, by using B16F10 melanoma cells as an experimental system, we directly explore the function of CAV1 in melanoma tumor growth and metastasis. We first show that CAV1 expression promotes proliferation, whereas it suppresses migration and invasion of B16F10 cells in vitro. When orthotopically implanted in the skin of mice, B16F10 cells expressing CAV1 form tumors that are similar in size to their control counterparts. An experimental metastasis assay shows that CAV1 expression suppresses the ability of B16F10 cells to form lung metastases in C57Bl/6 syngeneic mice. Additionally, CAV1 protein and mRNA levels are found to be significantly reduced in human metastatic melanoma cell lines and human tissue from metastatic lesions. Finally, we show that following integrin activation, B16F10 cells expressing CAV1 display reduced expression levels and activity of FAK and Src proteins. Furthermore, CAV1 expression markedly reduces the expression of integrin ?(3) in B16F10 melanoma cells. In summary, our findings provide experimental evidence that CAV1 may function as an antimetastatic gene in malignant melanoma.

| S-EPMC2948597 | biostudies-literature

MUC5AC interactions with integrin ?4 enhances the migration of lung cancer cells through FAK signaling.

Project description:MUC5AC is a secretory mucin aberrantly expressed in various cancers. In lung cancer, MUC5AC is overexpressed in both primary and metastatic lesions; however, its functional role is not well understood. The present study was aimed at evaluating mechanistic role of MUC5AC on metastasis of lung cancer cells. Clinically, the overexpression of MUC5AC was observed in lung cancer patient tissues and was associated with poor survival. In addition, the overexpression of Muc5ac was also observed in genetically engineered mouse lung adenocarcinoma tissues (Kras(G12D); Trp53(R172H/+); AdCre) in comparison with normal lung tissues. Our functional studies showed that MUC5AC knockdown resulted in significantly decreased migration in two lung cancer cell lines (A549 and H1437) as compared with scramble cells. Expression of integrins (?5, ?1, ?3, ?4 and ?5) was decreased in MUC5AC knockdown cells. As both integrins and MUC5AC have a von Willebrand factor domain, we assessed for possible interaction of MUC5AC and integrins in lung cancer cells. MUC5AC strongly interacted only with integrin ?4. The co-localization of MUC5AC and integrin ?4 was observed both in A549 lung cancer cells as well as genetically engineered mouse adenocarcinoma tissues. Activated integrins recruit focal adhesion kinase (FAK) that mediates metastatic downstream signaling pathways. Phosphorylation of FAK (Y397) was decreased in MUC5AC knockdown cells. MUC5AC/integrin ?4/FAK-mediated lung cancer cell migration was confirmed through experiments utilizing a phosphorylation (Y397)-specific FAK inhibitor. In conclusion, overexpression of MUC5AC is a poor prognostic marker in lung cancer. MUC5AC interacts with integrin ?4 that mediates phosphorylation of FAK at Y397 leading to lung cancer cell migration.

| S-EPMC5745007 | biostudies-literature

AKR1B10 promotes breast cancer metastasis through integrin α5/δ-catenin mediated FAK/Src/Rac1 signaling pathway.

Project description:Aldo-keto reductase 1B10 (AKR1B10) is not expressed in normal breast, but upregulated in primary and metastatic breast cancers, being a negative prognostic factor. This study characterized the molecular mechanisms of AKR1B10-promoted breast cancer metastasis. Ectopic expression of AKR1B10 in breast cancer cells MCF-7 and MDA-MB-231 or siRNA-mediated silencing in BT-20 cells affected cell adhesion, migration and invasion in cell culture, and metastasis to the lung in the nude mice through upregulation of integrin α5 and δ-catenin. Silencing of integrin α5 or δ-catenin eradicated the cell adhesion and migration enhanced by AKR1B10, both of which acted synergistically. In these cells, the integrin α5 mediated focal adhesion kinase (FAK) signaling pathway was activated by AKR1B10, which, along with δ-catenin, stimulated Rac1-mediated cell migration and movement. In human primary and lymph node metastatic breast cancer, AKR1B10, integrin α5 and δ-catenin were correlatively upregulated with r=0.645 (p<0.0001) and r=0.796 (p<0.0001), respectively. These data suggest that AKR1B10 promotes breast cancer metastasis through activation of the integrin α5 and δ-catenin mediated FAK/Src/Rac1 signaling pathway.

| S-EPMC5190059 | biostudies-literature

NPTX1 promotes metastasis via integrin/FAK signaling in gastric cancer.

Project description:PurposeThis study aimed to investigate the effect of NPTX1 on the prognosis of gastric cancer (GC), as well as the metastatic process in GC.Materials and methodsThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analyze the association between NPTX1 expression and prognosis in GC. Quantitative real-time polymerase chain reaction and Western blots were applied to examine the expression of NPTX1 in GC cell lines and expression of genes in downstream pathways. The role of NPTX1 on the migration, invasion, adhesion, and proliferation of GC cell lines was investigated with the transwell assay, the adhesion assay, and the MTT assay. Immunofluorescence staining was used to observe the effect of NPTX1 knockdown on the morphology of cells.ResultsAccording to the review of TCGA and GEO databases of GC, we found that the expression of NPTX1 increased in cancer tissues and high NPTX1 expression was correlated with poor overall survival, which was associated with lymph node stage in clinicopathologic parameters. Knockdown of NPTX1 attenuated the migration, invasion, and adhesion abilities of GC cells. According to gene set enrichment analysis, NPTX1 was found to be positively related to integrin and focal adhesion (FA). Additionally, NPTX1 knockdown decreased the expression of integrin ?1 and integrin ?7, followed by deregulation of the expression of p-Src, p-Akt, p-Erk, MMP2, and MMP7, as well as inhibiting the formation of FA complexes and decreasing the length of pseudopods in GC cells.ConclusionOur study provides strong evidence that NPTX1 plays a crucial role in promoting metastasis and acts as a prognostic indicator in GC.

| S-EPMC6472287 | biostudies-literature

TIMP1 preserves the blood–brain barrier through interacting with CD63/integrin ?1 complex and regulating downstream FAK/RhoA signaling.

Project description:Graphical abstractTIMP1 acts as an extracellular signal inducer that regulates endothelial barrier integrity through its interaction with CD63/integrin ?1 complex on the cell surface and integrin signaling activation. The subsequent inhibition of RhoA activity stabilizes cytoskeleton, providing protection against endothelial barrier disruption, which is induced by permeability-increasing mediators.Image 1

| S-EPMC7332810 | biostudies-literature

The microRNA-200/Zeb1 axis regulates ECM-dependent ?1-integrin/FAK signaling, cancer cell invasion and metastasis through CRKL.

Project description:Tumor cell metastasis is a complex process that has been mechanistically linked to the epithelial-mesenchymal transition (EMT). The double-negative feedback loop between the microRNA-200 family and the Zeb1 transcriptional repressor is a master EMT regulator, but there is incomplete understanding of how miR-200 suppresses invasion. Our recent efforts have focused on the tumor cell-matrix interactions essential to tumor cell activation. Herein we utilized both our Kras/p53 mutant mouse model and human lung cancer cell lines to demonstrate that upon miR-200 loss integrin ?1-collagen I interactions drive 3D in vitro migration/invasion and in vivo metastases. Zeb1-dependent EMT enhances tumor cell responsiveness to the ECM composition and activates FAK/Src pathway signaling by de-repression of the direct miR-200 target, CRKL. We demonstrate that CRKL serves as an adaptor molecule to facilitate focal adhesion formation, mediates outside-in signaling through Itg?1 to drive cell invasion, and inside-out signaling that maintains tumor cell-matrix contacts required for cell invasion. Importantly, CRKL levels in pan-cancer TCGA analyses were predictive of survival and CRKL knockdown suppressed experimental metastases in vivo without affecting primary tumor growth. Our findings highlight the critical ECM-tumor cell interactions regulated by miR-200/Zeb1-dependent EMT that activate intracellular signaling pathways responsible for tumor cell invasion and metastasis.

| S-EPMC4700473 | biostudies-literature

Glucose Transporter 1 Promotes the Malignant Phenotype of Non-Small Cell Lung Cancer through Integrin ?1/Src/FAK Signaling.

Project description:Background: Glucose transporter 1 (GLUT1) is the main factor of Warburg effect, which is associated with poor prognosis in many tumors. However, the underlying molecular mechanism of GLUT1 in the progression of non-small cell lung cancer (NSCLC) is unclear. Methods: We used quantitative real-time PCR to detect GLUT1 mRNA expression in bronchial brushing samples and performed Western Blot and biological behavior testing to check the effect of GLUT1 on NSCLC cell proliferation, migration, invasion and apoptosis. Results: We found that the C(t) normalized value of GLUT1 in malignant bronchial brushing samples was significantly higher than that in benign samples (P<0.05). GLUT1 significantly increased the expressions of cyclin A, cyclin D1, cyclin E, cyclin dependent kinase 2 (CDK2), CDK4, CDK6 and matrix metalloproteinase 2 (MMP2), but decreased the expressions of p53 and p130 in NSCLC cells. The biological behavior testing indicated that GLUT1 enhanced NSCLC cell proliferation, invasion and migration but inhibited cell apoptosis. In addition, GLUT1 upregulated the expression of integrin ?1 and promoted the phosphorylation of focal adhesion kinase (FAK, phosphorylation at Tyr576/577) and Src (Src phosphorylation at Tyr530). siRNA knock down of integrin ?1 expression suppressed GLUT1 induced NSCLC cell biological behavior, as well as the phosphorylation of FAK and Src. Conclusion: Taken together, our data confirms that GLUT1 promotes the malignant phenotype of NSCLC through integrin ?1/Src/FAK signaling, which provides a new therapeutic target for the treatment and research of lung cancer.

| S-EPMC6775508 | biostudies-literature

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