Epigenetic associations of GPNMB rs199347 variant with alcohol consumption in Parkinson's disease.

Introduction: Alcohol consumption can induce a neuroinflammatory response and contribute to the progression of neurodegeneration. However, its association with Parkinson's disease (PD), the second most common neurodegenerative disorder, remains undetermined. Recent studies suggest that the glycoprotein non-metastatic melanoma protein B (GPNMB) is a potential biomarker for PD. We evaluated the association of rs199347, a variant of the GPNMB gene, with alcohol consumption and methylation upstream of GPNMB. Methods: We retrieved genetic and DNA methylation data obtained from participants enrolled in the Taiwan Biobank (TWB) between 2008 and 2016. After excluding individuals with incomplete or missing information about potential PD risk factors, we included 1,357 participants in our final analyses. We used multiple linear regression to assess the association of GPNMB rs199347 and chronic alcohol consumption (and other potential risk factors) with GPNMB cg17274742 methylation. Results: There was no difference between the distribution of GPNMB rs199347 genotypes between chronic alcohol consumers and the other study participants. A significant interaction was observed between the GPNMB rs199347 variant and alcohol consumption (p = 0.0102) concerning cg17274742 methylation. Compared to non-chronic alcohol consumers with the AA genotype, alcohol drinkers with the rs199347 GG genotype had significantly lower levels (hypomethylation) of cg17274742 (p = 0.0187). Conclusion: Alcohol consumption among individuals with the rs199347 GG genotype was associated with lower levels of cg17274742 methylation, which could increase expression of the GPNMB gene, an important neuroinflammatory-related risk gene for PD.

Glycoprotein non-metastatic melanoma protein B (GPNMB): An attractive target in atherosclerosis.

Atherosclerosis (AS), the leading cause of cardiovascular diseases, is heavily influenced by inflammation, lipid accumulation, autophagy, and aging. The expression of glycoprotein non-metastatic melanoma B (GPNMB) has been observed to correlate with lipid content, inflammation, and aging, progressively increasing as atherosclerosis advances through its various stages, from baseline to early and advanced phases. However, the interaction between GPNMB and AS is controversial. Knockout of GPNMB has been shown to increase atherosclerotic plaque burden in mice. Conversely, targeted elimination of GPNMB-positive cells reduced atherosclerotic burden. These seemingly contradictory findings underscore the complexity of the issue and highlight the need for further research to reconcile these discrepancies and to elucidate the precise role of GPNMB in the pathogenesis of AS.

Ethnic Variations in the Levels of Bone Biomarkers (Osteoprostegerin, Receptor Activator of Nuclear Factor Kappa-Β Ligand and Glycoprotein Non-Metastatic Melanoma Protein B) in People with Type 2 Diabetes.

The global incidence of Type 2 diabetes (T2D) is on the rise, fueled by factors such as obesity, sedentary lifestyles, socio-economic factors, and ethnic backgrounds. T2D is a multifaceted condition often associated with various health complications, including adverse effects on bone health. This study aims to assess key biomarkers linked to bone health and remodeling-Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), and Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB)-among individuals with diabetes while exploring the impact of ethnicity on these biomarkers. A cross-sectional analysis was conducted on a cohort of 2083 individuals from diverse ethnic backgrounds residing in Kuwait. The results indicate significantly elevated levels of these markers in individuals with T2D compared to non-diabetic counterparts, with OPG at 826.47 (405.8) pg/mL, RANKL at 9.25 (17.3) pg/mL, and GPNMB at 21.44 (7) ng/mL versus 653.75 (231.7) pg/mL, 0.21 (9.94) pg/mL, and 18.65 (5) ng/mL in non-diabetic individuals, respectively. Notably, this elevation was consistent across Arab and Asian populations, except for lower levels of RANKL observed in Arabs with T2D. Furthermore, a positive and significant correlation between OPG and GPNMB was observed regardless of ethnicity or diabetes status, with the strongest correlation (r = 0.473, p < 0.001) found among Arab individuals with T2D. Similarly, a positive and significant correlation between GPNMB and RANKL was noted among Asian individuals with T2D (r = 0.401, p = 0.001). Interestingly, a significant inverse correlation was detected between OPG and RANKL in non-diabetic Arab individuals. These findings highlight dysregulation in bone remodeling markers among individuals with T2D and emphasize the importance of considering ethnic variations in T2D-related complications. The performance of further studies is warranted to understand the underlying mechanisms and develop interventions based on ethnicity for personalized treatment approaches.

Glycoprotein Non-metastatic Melanoma Protein B (GPNMB) Protects Against Neuroinflammation and Neuronal Loss in Pilocarpine-induced Epilepsy via the Regulation of Microglial Polarization.

Epilepsy is a progressive neurodegenerative disease highlighted by recurrent seizures, neuroinflammation, and the loss of neurons. Microglial dysfunction is commonly found in epileptic foci and contributes to neuroinflammation in the initiation and progression of epilepsy. Glycoprotein non-metastatic melanoma protein B (GPNMB), a transmembrane glycoprotein, has been involved in the microglial activation and neuroinflammation response. The present study investigated the functional significance of GPNMB in epilepsy. A proven model of epilepsy was established by intraperitoneal injection of pilocarpine to male Sprague Dawley rats. Lentivirus vectors carrying GPNMB or GPNMB short hairpin RNA (shGPNMB) were injected into the hippocampus to induce overexpression or knockdown of GPNMB. GPNMB expression was significantly upregulated and overexpression of GPNMB in the hippocampus reduced seizure activity and neuronal loss after status epilepticus (SE). We here focused on the effects of GPNMB deficiency on neuronal injury and microglia polarization 28 days after SE. GPNMB knockdown accelerated neuronal damage in the hippocampus, evidenced by increased neuron loss and neuronal cell apoptosis. Following GPNMB knockdown, M1 polarization (iNOS) and secretion of pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α were increased, and M2 polarization (Arg1) and secretion of anti-inflammatory cytokines IL-4, IL-10, and TGF-ß were decreased. BV2 cells were used to further confirm the regulatory role of GPNMB in modulating phenotypic transformations and inflammatory cytokine expressions in microglia. In conclusion, these results indicated that GPNMB suppressed epilepsy through repression of hippocampal neuroinflammation, suggesting that GPNMB might be considered the potential neurotherapeutic target for epilepsy management and play a protective role against epilepsy by modulating the polarization of microglia.

GPNMB Expression Associates with Inferior Prognosis in Patients with Small Cell Lung Cancer.

Purpose: Small cell lung cancer (SCLC) is widely recognized for its propensity for early and frequent metastases, which contribute to its status as a refractory malignancy. While the high expression of GPNMB in SCLC is well-documented, the precise correlation between GPNMB expression and the prognosis of SCLC remains undetermined. Methods: HTG Edge-seq was used to screen the differential gene expression between primary SCLC lesions and paired metastatic lymph nodes (LN). The plasma concentration of GPNMB was measured using enzyme-linked immunosorbent assay (ELISA). The relationship between GPNMB concentration and clinical characteristics, as well as overall survival (OS) was assessed. One-to-one propensity score matching (PSM) was performed to reduce bias from confounding factors between groups. The invasive, migratory, proliferative, and apoptotic abilities of SCLC cells were evaluated using migration and matrigel invasion assays, CCK8 assay and flow cytometry respectively. Results: GPNMB exhibited a significant up-regulation in LN compared to primary SCLC lesions as determined by HTG Edge-seq. Furthermore, patients with extensive disease demonstrated a significantly elevated plasma GPNMB concentration compared to those with local disease (P = 0.043). Additionally, patients with a high baseline plasma GPNMB level exhibited a shorter OS (10.32 vs. 16.10 months, P = 0.0299). Following PSM analysis, the statistical significance of the difference between the two groups persisted (9.43 vs. 15.27 months, P = 0.0146). Notably, both univariate and multivariate analyses confirmed that higher expression of GPNMB served as an independent biomarker for OS before PSM (P = 0.033, HR = 2.304) and after PSM (P = 0.003, HR = 6.190). Additionally, our study revealed that the inhibition of GPNMB expression through the use of siRNA effectively diminished the metastatic and proliferative capabilities of SCLC. Furthermore, this inhibition resulted in an enhanced ability to induce apoptosis. Conclusions: In light of our findings, it can be inferred that the expression of GPNMB is linked to metastasis and an unfavorable prognosis, thus suggesting its potential as a novel therapeutic target in the treatment of SCLC.

Glycoprotein non-metastatic melanoma protein B promotes tumor growth and is a biomarker for lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including glycoprotein non-metastatic melanoma protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB's unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here, we establish that GPNMB expression is dependent on mTORC1 signaling, and that GPNMB regulates TSC2-null tumor cell invasion in vitro. Further, we demonstrate that GPNMB enhances TSC2-null xenograft tumor growth in vivo, and that ectodomain release is required for this xenograft growth. We also show that GPNMB's ectodomain is released from the cell surface of TSC2-null cells by proteases ADAM10 and 17, and we identify the protease target sequence on GPNMB. Finally, we demonstrate that GPNMB's ectodomain is present at higher levels in LAM patient serum compared to healthy controls and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.

GPNMB Biomarker Levels in GBA1 Carriers with Lewy Body Disorders.

BACKGROUND: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease. OBJECTIVE: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype. METHODS: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status. RESULTS: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status. CONCLUSIONS: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Potential imaging targets in primary head and neck squamous cell carcinoma and lymph node metastases.

PURPOSE: To investigate glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) as potential fluorescent imaging markers by comparing their protein expression to epidermal growth factor receptor (EGFR). MATERIALS AND METHODS: Thirty-eight paired samples of untreated head and neck squamous cell carcinoma (HNSCC) primary tumours (PT) and corresponding synchronous lymph node metastases (LNM) were selected. After immunohistochemical staining, expression was assessed and compared by the percentage of positive tumour cells. Data were analysed using the Mann-Whitney test, effect sizes (ESr) and Spearman's correlation coefficient (r). RESULTS: GPNMB expression was observed in 100 % of PT, and median 80 % (range 5-100 %) of tumour cells, VEGF in 92 % and 60 % (0-100 %), EGFR in 87 % and 60 % (0-100 %) respectively. In corresponding LNM, GPNMB expression was observed in 100 % of LNM and median 90 % (20-100 %) of tumour cells, VEGF in 87 % and 65 % (0-100 %), and EGFR in 84 % and 35 % (0-100 %). A positive correlation was found between expression in PT and LNM for GPNMB (r = 0.548) and EGFR (r = 0.618) (p < 0.001), but not for VEGF (r = -0.020; p = 0.905). GPNMB expression was present in a higher percentage of tumour cells compared to EGFR in PT (p = 0.015, ESr = -0.320) and in LNM (p < 0.001, ESr = -0.478), while VEGF was not (p = 1.00, ESr = -0.109 and - 0.152, respectively). CONCLUSION: GPNMB expression is higher than EGFR in untreated HNSCC PT and corresponding LNM, while VEGF expression is comparable to EGFR. GPNMB is a promising target for fluorescent imaging in HNSCC.

Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma.

Tumor-associated microglia and blood-derived macrophages (TAMs) play a central role in modulating the immune suppressive microenvironment in glioma. Here, we show that GPNMB is predominantly expressed by TAMs in human glioblastoma multiforme and the murine RCAS-PDGFb high grade glioma model. Loss of GPNMB in the in vivo tumor microenvironment results in significantly smaller tumor volumes and generates a pro-inflammatory innate and adaptive immune cell microenvironment. The impact of host-derived GPNMB on tumor growth was confirmed in two distinct murine glioma cell lines in organotypic brain slices from GPNMB-KO and control mice. Using published data bases of human glioma, the elevated levels in TAMs could be confirmed and the GPNMB expression correlated with a poorer survival.

Chronically activated microglia in ALS gradually lose their immune functions and develop unconventional proteome.

Neuroinflammation and chronic activation of microglial cells are the prominent features of amyotrophic lateral sclerosis (ALS) pathology. While alterations in the mRNA profile of diseased microglia have been well documented, the actual microglia proteome remains poorly characterized. Here we performed a functional characterization together with proteome analyses of microglial cells at different stages of disease in the SOD1-G93A model of ALS. Functional analyses of microglia derived from the lumbar spinal cord of symptomatic mice revealed: (i) remarkably high mitotic index (close to 100% cells are Ki67+) (ii) significant decrease in phagocytic capacity when compared to age-matched control microglia, and (iii) diminished response to innate immune challenges in vitro and in vivo. Proteome analysis revealed a development of two distinct molecular signatures at early and advanced stages of disease. While at early stages of disease, we identified several proteins implicated in microglia immune functions such as GPNMB, HMBOX1, at advanced stages of disease microglia signature at protein level was characterized with a robust upregulation of several unconventional proteins including rootletin, major vaults proteins and STK38. Upregulation of GPNMB and rootletin has been also found in the spinal cord samples of sporadic ALS. Remarkably, the top biological functions of microglia, in particular in the advanced disease, were not related to immunity/immune response, but were highly enriched in terms linked to RNA metabolism. Together, our results suggest that, over the course of disease, chronically activated microglia develop unconventional protein signatures and gradually lose their immune identity ultimately turning into functionally inefficient immune cells.

Glycoprotein nonmetastatic melanoma protein B impacts the malignant potential of bladder cancer cells through its hem-immunoreceptor tyrosine-based activation motif.

Bladder cancer is one of the most common cancers among men worldwide. Although multiple genomic mutations and epigenetic alterations have been identified, an efficacious molecularly targeted therapy has yet to be established. Therefore, a novel approach is anticipated. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that is highly expressed in various cancers. In this study, we evaluated bladder cancer patient samples and found that GPNMB protein abundance is associated with high-grade tumors, and both univariate and multivariate analyses showed that GPNMB is a prognostic factor. Furthermore, the prognosis of patients with high GPNMB levels was significantly poorer in those with nonmuscle invasive bladder cancer (NMIBC) than in those with muscle invasive bladder cancer (MIBC). We then demonstrated that knockdown of GPNMB in MIBC cell lines with high GPNMB inhibits cellular migration and invasion, whereas overexpression of GPNMB further enhances cellular migration and invasion in MIBC cell lines with originally low GPNMB. Therefore, we propose that GPNMB is one of multiple driver molecules in the acquisition of cellular migratory and invasive potential in bladder cancers. Moreover, we revealed that the tyrosine residue in the hemi-immunoreceptor tyrosine-based activation motif (hemITAM) is required for GPNMB-induced cellular motility.

Truncated GPNMB, a microglial transmembrane protein, serves as a scavenger receptor for oligomeric ß-amyloid peptide1-42 in primary type 1 microglia.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is up-regulated in one subtype of microglia (MG) surrounding senile plaque depositions of amyloid-beta (Aß) peptides. However, whether the microglial GPNMB can recognize the fibrous Aß peptides as ligands remains unknown. In this study, we report that the truncated form of GPNMB, the antigen for 9F5, serves as a scavenger receptor for oligomeric Aß1-42 (o-Aß1-42) in rat primary type 1 MG. 125I-labeled o-Aß1-42 exhibited specific and saturable endosomal/lysosomal degradation in primary-cultured type 1 MG from GPNMB-expressing wild-type mice, whereas the degradation activity was markedly reduced in cells from Gpnmb-knockout mice. The Gpnmb-siRNA significantly inhibits the degradation of 125I-o-Aß1-42 by murine microglial MG5 cells. Therefore, GPNMB contributes to mouse MG's o-Aß1-42 clearance. In rat primary type 1 MG, the cell surface expression of truncated GPNMB was confirmed by a flow cytometric analysis using a previously established 9F5 antibody. 125I-labeled o-Aß1-42 underwent endosomal/lysosomal degradation by rat primary type 1 MG in a dose-dependent fashion, while the 9F5 antibody inhibited the degradation. The binding of 125I-o-Aß1-42 to the rat primary type 1 MG was inhibited by 42% by excess unlabeled o-Aß1-42, and by 52% by the 9F5 antibody. Interestingly, the 125I-o-Aß1-42 degradations by MG-like cells from human-induced pluripotent stem cells was inhibited by the 9F5 antibody, suggesting that truncated GPNMB also serve as a scavenger receptor for o-Aß1-42 in human MG. Our study demonstrates that the truncated GPNMB (the antigen for 9F5) binds to oligomeric form of Aß1-42 and functions as a scavenger receptor on MG, and 9F5 antibody can act as a blocking antibody for the truncated GPNMB.

GPNMB Modulates Autophagy to Enhance Functional Recovery After Spinal Cord Injury in Rats.

Spinal cord injury (SCI) severely affects the quality of life and autonomy of patients, and effective treatments are currently lacking. Autophagy, an essential cellular metabolic process, plays a crucial role in neuroprotection and repair after SCI. Glycoprotein non-metastatic melanoma protein B (GPNMB) has been shown to promote neural regeneration and synapse reconstruction, potentially through the facilitation of autophagy. However, the specific role of GPNMB in autophagy after SCI is still unclear. In this study, we utilized the spinal cord transection method to establish SCI rats model and overexpressed GPNMB using adenoviral vectors. We assessed tissue damage using hematoxylin and eosin (H&E) and Nissl staining, and observed cell apoptosis using TUNEL staining. We evaluated the inflammatory response by measuring inflammatory factors using enzyme-linked immunosorbent assay (ELISA). In addition, we measured reactive oxygen species (ROS) levels using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), and assessed oxidative stress levels by measuring malondialdehyde (MDA) and glutathione (GSH) using ELISA. To evaluate autophagy levels, we performed immunofluorescence staining for the autophagy marker Beclin-1 and conducted Western blot analysis for autophagy-related proteins. We also assessed limb recovery through functional evaluation. Meanwhile, we induced cell injury using lipopolysaccharide (LPS) and added an autophagy inhibitor to verify the impact of GPNMB on SCI through autophagy modulation. The results demonstrated that GPNMB alleviated the inflammatory response, reduced oxidative stress levels, inhibited cell apoptosis, and promoted autophagy following SCI. Inhibiting autophagy reversed the effects of GPNMB. These findings suggest that GPNMB promotes neural injury repair after SCI, potentially through attenuating the inflammatory response, reducing oxidative stress, and inhibiting cell apoptosis.

Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Immunohistochemistry Can Be a Useful Ancillary Tool to Identify Perivascular Epithelioid Cell Tumor.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that express smooth muscle and melanocytic makers. Diagnosis of PEComas can be challenging due to focal or lost expression of traditional immunohistochemical markers, limited availability of molecular testing, and morphological overlap with much more common smooth muscle tumors. This study evaluates the use of glycoprotein nonmetastatic melanoma protein B (GPNMB) immunohistochemical staining as a surrogate marker for TSC1/2/MTOR alteration or TFE3 rearrangement to differentiate PEComas from other mesenchymal tumors. Cathepsin K was also assessed for comparison. A total of 399 tumors, including PEComas, alveolar soft part sarcomas, and other histologic PEComa mimics, were analyzed using GPNMB and cathepsin K immunohistochemistry. GPNMB expression was seen in all PEComas and alveolar soft part sarcomas with the majority showing diffuse and moderate-to-strong labeling, whereas other sarcomas were negative or showed focal labeling. When a cutoff of diffuse and at least moderate staining was used, GPNMB demonstrated 95% sensitivity and 97% specificity in distinguishing PEComas from leiomyosarcoma, well-differentiated/dedifferentiated liposarcomas, and undifferentiated pleomorphic sarcomas. Cathepsin K with a cutoff of any labeling had lower sensitivity (78%) and similar specificity (94%) to GPNMB. This study highlights GPNMB as a highly sensitive marker for PEComas and suggests its potential use as an ancillary tool within a panel of markers for accurate classification of these tumors.

The association between plasma GPNMB and Parkinson's disease and multiple system atrophy.

AIMS: Parkinson's disease (PD), as the second most common neurodegenerative disorder, often presents diagnostic challenges in differentiation from other forms of Parkinsonism. Recent studies have reported an association between plasma glycoprotein nonmetastatic melanoma protein B (pGPNMB) and PD. METHODS: A retrospective study was conducted, comprising 401 PD patients, 111 multiple system atrophy (MSA) patients, 13 progressive supranuclear palsy (PSP) patients and 461 healthy controls from the Chinese Han population, with an assessment of pGPNMB levels. RESULTS: The study revealed that pGPNMB concentrations were significantly lower in PD and MSA patients compared to controls (area under the receiver operating characteristics curve (AUC) 0.62 and 0.74, respectively, P < 0.0001 for both), but no difference was found in PSP patients compared to controls (P > 0.05). Interestingly, the level of pGPNMB was significantly higher in PD patients than in MSA patients (AUC = 0.63, P < 0.0001). Furthermore, the study explored the association between pGPNMB levels and disease severity in PD and MSA patients, revealing a positive correlation in PD patients but not in MSA patients with both disease severity and cognitive impairment. CONCLUSION: This study successfully replicated prior findings, demonstrating an association between pGPNMB levels and disease severity, and also identified a correlation with cognitive impairment in PD patients of the Chinese Han population. Additionally, this study is the first to identify a significant difference in pGPNMB levels between MSA, PD, and normal controls. The data provide new evidence supporting the potential role of pGPNMB in the diagnosis and differential diagnosis of Parkinsonism.

HOMER3 promotes liver hepatocellular carcinoma cancer progression by -upregulating EZH2 and mediating miR-361/GPNMB axis.

Liver hepatocellular carcinoma (LIHC) is among the most lethal human cancers. Studies have shown that Homer scaffold protein 3 (HOMER3) plays important roles in various diseases and cancers, but its biological function and molecular mechanism in LIHC have never been investigated. Our study discovered the aberrantly high expression of HOMER3 and its promising diagnostic and prognostic significance in LIHC. Functionally, HOMER3 knockdown inhibited the proliferative and migrative abilities of LIHC cells and tumor growth in vivo. Mechanically, HOMER3 mediated the aggressiveness of LIHC cells via GPNMB. Meanwhile, miR-361 directly targeted GPNMB and attenuated LIHC progression by suppressing GPNMB expression. The regulatory effect of HOMER3 during LIHC progression was exerted through the miR-361/GPNMB axis. Furthermore, EZH2 supplementation or miR-361 depletion effectively abated the tumor-suppressive effect of HOMER3 knockdown on LIHC progression. In conclusion, HOMER3 mediated LIHC progression through the EZH2/miR-361/GPNMB axis.

PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway.

BACKGROUND: Ischemic stroke is the second leading cause of death worldwide, and neuroinflammation has been recognized as a critical player in its progression. Meanwhile, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) has been demonstrated to inhibit inflammatory response. However, the effects of PCSK9i on ischemic stroke remain unclear and require further investigation. METHODS: Temporary middle cerebral artery occlusion (tMCAO) was performed to establish animal models of ischemic stroke in C57BL/6 mice. The PCSK9i were administered subcutaneously after 2 h tMCAO. Neurological function and cerebral infarct volume were measured by mNSS and TTC staining, respectively. RNA-seq was performed to investigate the changes in mechanistic pathways. Western blotting and immunofluorescence were applied to detect expression of GPNMB, CD44, IL-6, and iNOS. RESULTS: Treatment with PCSK9i significantly improved neurological deficits and reduced the volume of cerebral infarction. PCSK9i suppressed neuroinflammation by activating the GPNMB/CD44 signaling pathway, further exerting their protective effects. CONCLUSION: Taken together, treatment with PCSK9i is an effective way to prevent ischemic stroke-induced brain injury.

Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease.

BACKGROUND: Alterations in progranulin (PGRN) expression are associated with multiple neurodegenerative diseases (NDs), including frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and lysosomal storage disorders (LSDs). Recently, the loss of PGRN was shown to result in endo-lysosomal system dysfunction and an age-dependent increase in the expression of another protein associated with NDs, glycoprotein non-metastatic B (GPNMB). MAIN BODY: It is unclear what role GPNMB plays in the context of PGRN insufficiency and how they interact and contribute to the development or progression of NDs. This review focuses on the interplay between these two critical proteins within the context of endo-lysosomal health, immune function, and inflammation in their contribution to NDs. SHORT CONCLUSION: PGRN and GPNMB are interrelated proteins that regulate disease-relevant processes and may have value as therapeutic targets to delay disease progression or extend therapeutic windows.

MDSC suppresses T cell antitumor immunity in CAC via GPNMB in a MyD88-dependent manner.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) played an essential role in tumor microenvironment to suppress host antitumor immunity and help cancer cells escape immune surveillance. However, the molecular mechanism behind tumor evasion mediated by MDSCs is not fully understood. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is considered to associate with tumor initiation, metastasis and angiogenesis. Blocking GPNMB function is a potentially valuable therapy for cancer by eliminating GPNMB+ MDSCs. Our previous study has proved that blockage the MyD88 signaling with the MyD88 inhibitor, TJ-M2010-5, may completely prevent the development of CAC in mice, accompanying with downregulation of GPNMB mRNA in the inhibitor-treated mice of CAC. METHODS: We here focus on the underlying the relationship between GPNMB function and MyD88 signaling pathway activation in MDSCs' antitumor activity in CAC. RESULTS: CAC development in the mouse model is associated with expanded GPNMB+ MDSCs by a MyD88-dependent pathway. The GPNMB expression on MDSCs is associated with MyD88 signaling activation. The inhibitory effect of MDSCs on T cell proliferation, activation and antitumor cytotoxicity in CAC is mediated by GPNMB in a MyD8-dependent manner. CONCLUSION: MyD88 signaling pathway plays an essential role in GPNMB+ MDSC-mediated tumor immune escape during CAC development and is a promising focus for revealing the mechanisms of MDSC that facilitate immunosuppression and tumor progression.

Glycoprotein non-metastatic melanoma protein B expression correlates with the prognosis of acute liver injury/failure.

Background: Glycoprotein non-metastatic melanoma protein B (GPNMB) is expressed in macrophages during recovery from acute liver injury (ALI) in carbon tetrachloride (CCl4)-induced liver injury model mice. In this retrospective study, we assessed whether GPNMB levels in the serum and injured liver correlate with liver injury severity and prognosis in patients with ALI or acute liver failure (ALF). Methods: The study involved 56 patients with ALI or ALF who visited the Kagoshima University Hospital. Serum GPNMB level was measured over time, and the localization, proportion, origin, and phenotype of GPNMB-expressing cells in the injured liver were assessed. Finally, the phenotypes of human monocyte-derived macrophages and peripheral blood mononuclear cells (PBMCs) of patients with ALI and ALF were analyzed. Results: Peak GPNMB levels were significantly higher in patients with ALF and hepatic encephalopathy (HE), as well as in those who underwent liver transplantation or died, than in others. The peak GPNMB level correlated with prothrombin activity, prothrombin time-international normalized ratio, Model for End-stage Liver Disease score, and serum hepatocyte growth factor level. GPNMB was expressed in CD68-positive macrophages, and its level increased with the severity of liver injury. The macrophages showed the same polarization as M2c macrophages induced with interleukin-10 from human monocytes. Moreover, PBMCs from patients with ALF exhibited an immunosuppressive phenotype. Conclusion: We found that GPNMB levels in the serum and injured liver, which increased in patients with ALF, especially in those with HE, correlated with the severity of liver injury and prognosis of ALI and ALF. Moreover, GPNMB-positive macrophages exhibited the M2c phenotype. Our results indicate that persistently high GPNMB levels may be a prognostic marker in patients with ALI and ALF.