Genetic deletion or tyrosine phosphatase inhibition of PTPRZ1 activates c-Met to up-regulate angiogenesis and lung adenocarcinoma growth.

Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) expressed in endothelial cells and required for stimulation of cell migration by vascular endothelial growth factor A165 (VEGFA165 ) and pleiotrophin (PTN). It is also over or under-expressed in various tumor types. In this study, we used genetically engineered Ptprz1-/- and Ptprz1+/+ mice to study mechanistic aspects of PTPRZ1 involvement in angiogenesis and investigate its role in lung adenocarcinoma (LUAD) growth. Ptprz1-/- lung microvascular endothelial cells (LMVEC) have increased angiogenic features compared with Ptprz1+/+ LMVEC, in line with the increased lung angiogenesis and the enhanced chemically induced LUAD growth in Ptprz1-/- compared with Ptprz1+/+ mice. In LUAD cells isolated from the lungs of urethane-treated mice, PTPRZ1 TP inhibition also enhanced proliferation and migration. Expression of beta 3 (ß3 ) integrin is decreased in Ptprz1-/- LMVEC, linked to enhanced VEGF receptor 2 (VEGFR2), c-Met tyrosine kinase (TK) and Akt kinase activities. However, only c-Met and Akt seem responsible for the enhanced endothelial cell activation in vitro and LUAD growth and angiogenesis in vivo in Ptprz1-/- mice. A selective PTPRZ1 TP inhibitor, VEGFA165 and PTN also activate c-Met and Akt in a PTPRZ1-dependent manner in endothelial cells, and their stimulatory effects are abolished by the c-Met TK inhibitor (TKI) crizotinib. Altogether, our data suggest that low PTPRZ1 expression is linked to worse LUAD prognosis and response to c-Met TKIs and uncover for the first time the role of PTPRZ1 in mediating c-Met activation by VEGFA and PTN.

Protein Tyrosine Phosphatase Receptor Zeta 1 as a Potential Target in Cancer Therapy and Diagnosis.

Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a type V transmembrane tyrosine phosphatase that is highly expressed during embryonic development, while its expression during adulthood is limited. PTPRZ1 is highly detected in the central nervous system, affecting oligodendrocytes' survival and maturation. In gliomas, PTPRZ1 expression is significantly upregulated and is being studied as a potential cancer driver and as a target for therapy. PTPRZ1 expression is also increased in other cancer types, but there are no data on the potential functional significance of this finding. On the other hand, low PTPRZ1 expression seems to be related to a worse prognosis in some cancer types, suggesting that in some cases, it may act as a tumor-suppressor gene. These discrepancies may be due to our limited understanding of PTPRZ1 signaling and tumor microenvironments. In this review, we present evidence on the role of PTPRZ1 in angiogenesis and cancer and discuss the phenomenal differences among the different types of cancer, depending on the regulation of its tyrosine phosphatase activity or ligand binding. Clarifying the involved signaling pathways will lead to its efficient exploitation as a novel therapeutic target or as a biomarker, and the development of proper therapeutic approaches.

Protein tyrosine phosphatase receptor-ζ1 deletion triggers defective heart morphogenesis in mice and zebrafish.

Protein tyrosine phosphatase receptor-ζ1 (PTPRZ1) is a transmembrane tyrosine phosphatase receptor highly expressed in embryonic stem cells. In the present work, gene expression analyses of Ptprz1-/- and Ptprz1+/+ mice endothelial cells and hearts pointed to an unidentified role of PTPRZ1 in heart development through the regulation of heart-specific transcription factor genes. Echocardiography analysis in mice identified that both systolic and diastolic functions are affected in Ptprz1-/- compared with Ptprz1+/+ hearts, based on a dilated left ventricular (LV) cavity, decreased ejection fraction and fraction shortening, and increased angiogenesis in Ptprz1-/- hearts, with no signs of cardiac hypertrophy. A zebrafish ptprz1-/- knockout was also generated and exhibited misregulated expression of developmental cardiac markers, bradycardia, and defective heart morphogenesis characterized by enlarged ventricles and defected contractility. A selective PTPRZ1 tyrosine phosphatase inhibitor affected zebrafish heart development and function in a way like what is observed in the ptprz1-/- zebrafish. The same inhibitor had no effect in the function of the adult zebrafish heart, suggesting that PTPRZ1 is not important for the adult heart function, in line with data from the human cell atlas showing very low to negligible PTPRZ1 expression in the adult human heart. However, in line with the animal models, Ptprz1 was expressed in many different cell types in the human fetal heart, such as valvar, fibroblast-like, cardiomyocytes, and endothelial cells. Collectively, these data suggest that PTPRZ1 regulates cardiac morphogenesis in a way that subsequently affects heart function and warrant further studies for the involvement of PTPRZ1 in idiopathic congenital cardiac pathologies.NEW & NOTEWORTHY Protein tyrosine phosphatase receptor ζ1 (PTPRZ1) is expressed in fetal but not adult heart and seems to affect heart development. In both mouse and zebrafish animal models, loss of PTPRZ1 results in dilated left ventricle cavity, decreased ejection fraction, and fraction shortening, with no signs of cardiac hypertrophy. PTPRZ1 also seems to be involved in atrioventricular canal specification, outflow tract morphogenesis, and heart angiogenesis. These results suggest that PTPRZ1 plays a role in heart development and support the hypothesis that it may be involved in congenital cardiac pathologies.

Pleiotrophin selectively binds to vascular endothelial growth factor receptor 2 and inhibits or stimulates cell migration depending on ανß3 integrin expression.

Pleiotrophin (PTN) has a moderate stimulatory effect on endothelial cell migration through ανß3 integrin, while it decreases the stimulatory effect of vascular endothelial growth factor A (VEGFA) and inhibits cell migration in the absence of ανß3 through unknown mechanism(s). In the present work, by using a multitude of experimental approaches, we show that PTN binds to VEGF receptor type 2 (VEGFR2) with a KD of 11.6 nM. Molecular dynamics approach suggests that PTN binds to the same VEGFR2 region with VEGFA through its N-terminal domain. PTN inhibits phosphorylation of VEGFR2 at Tyr1175 and still stimulates endothelial cell migration in the presence of a selective VEGFR2 tyrosine kinase inhibitor. VEGFR2 downregulation by siRNA or an anti-VEGFR2 antibody that binds to the ligand-binding VEGFR2 domain also induce endothelial cell migration, which is abolished by a function-blocking antibody against ανß3 or the peptide PTN112-136 that binds ανß3 and inhibits PTN binding. In cells that do not express ανß3, PTN decreases both VEGFR2 Tyr1175 phosphorylation and cell migration in a VEGFR2-dependent manner. Collectively, our data identify VEGFR2 as a novel PTN receptor involved in the regulation of cell migration by PTN and contribute to the elucidation of the mechanism of activation of endothelial cell migration through the interplay between VEGFR2 and ανß3.

Pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta as regulators of angiogenesis and cancer.

Pleiotrophin (PTN) is a secreted heparin-binding growth factor that through its receptor protein tyrosine phosphatase beta/zeta (RPTPß/ζ) has a significant regulatory effect on angiogenesis and cancer. PTN and RPTPß/ζ are over-expressed in several types of human cancers and regulate important cancer cell functions in vitro and cancer growth in vivo. This review begins with a brief introduction of PTN and the regulation of its expression. PTN receptors are described with special emphasis on RPTPß/ζ, which also interacts with and/or affects the function of other important targets for cancer therapy, such as vascular endothelial growth factor A, ανß3 and cell surface nucleolin. PTN biological activities related to angiogenesis and cancer are extensively discussed. Finally, up to date approaches of targeting PTN or RPTPß/ζ for cancer treatment are presented. Insights into the regulatory role of PTN/RPTPß/ζ on angiogenesis will be extremely beneficial for future development of alternative anti-angiogenic approaches in cancer therapy.

Synthesis of nοvel artemisinin dimers with polyamine linkers and evaluation of their potential as anticancer agents.

The natural product artemisinin and derivatives thereof are currently considered as the drugs of choice for the treatment of malaria. At the same time, a significant number of such drugs have also shown interesting anticancer activity. In the context of the present research work, artemisinin was structurally modified and anchored to naturally occurring polyamines to afford new artemisinin dimeric conjugates whose potential anticancer activity was evaluated. All artemisinin conjugates tested were more effective than artemisinin itself in decreasing the number of MCF7 breast cancer cells. The effect required conjugation and was not due to the artemisinin analogue or the polyamine, alone or in combination. To elucidate potential mechanism of action, we used the most effective conjugates 6, 7, 9 and 12 and found that they decreased expression and secretion of the angiogenic growth factor pleiotrophin by the cancer cells themselves, and inhibited angiogenesis in vivo and endothelial cell growth in vitro. These data suggest that the new artemisinin dimers are good candidates for the development of effective anticancer agents.

Genetic detection of hantaviruses in rodents, Albania.

In order to have a first insight into the epidemiology of hantaviruses in Albania, 263 small mammals (248 rodents, 15 insectivores) were captured in 352 locations in 29 districts and tested for hantavirus infection. Dobrava-Belgrade virus (DOBV) was detected in 10 of 148 (6.7%) Apodemus flavicollis rodents. DOBV-positive A. flavicollis were detected in six districts (Diber, Korce, Kolonje, Librazhd, Pogradec, and Vlore). The obtained nucleotide sequences were highly similar to each other and to DOBV sequences from northwestern Greece. Understanding the epidemiology of hantaviruses and identifying the endemic foci enables the public health strategies to minimize the risk of human infection. J. Med. Virol. 88:1309-1313, 2016. © 2016 Wiley Periodicals, Inc.

Comparing Abbott m2000 RealTime HIV test and Roche COBAS Ampliprep/COBAS Taqman HIV test, v2.0 in treated HIV-1 B and non-B subjects with low viraemia.

Viral load testing is a valuable tool in HIV clinical care and research. Discrepancies among diverse viral load assays, especially with regard to non-B HIV-1 subtypes have been reported. Our study aimed to explore the impact of HIV subtype (B versus non-B) on the agreement between CAP/CTM, v2.0 and m2000 RealTime in treated HIV patients, focusing on low viral loads (<200 copies/ml). Our findings indicate that there is a significant difference in the performance of the compared assays in the low-viremic range and non-B subtypes, suggesting that a single assay should be used for follow-up.

Effects of mechanical loading on the expression of pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in a rat spinal deformity model.

Mechanical loading of the spine is a major causative factor of degenerative changes and causes molecular and structural changes in the intervertebral disc (IVD) and the vertebrae end plate (EP). Pleiotrophin (PTN) is a growth factor with a putative role in bone remodeling through its receptor protein tyrosine phosphatase beta/zeta (RPTPß/ζ). The present study investigates the effects of strain on PTN and RPTPß/ζ protein expression in vivo. Tails of eight weeks old Sprague-Dawley rats were subjected to mechanical loading using a mini Ilizarov external apparatus. Rat tails untreated (control) or after 0 degrees of compression and 10°, 30° and 50° of angulation (groups 0, I, II and III respectively) were studied. PTN and RPTPß/ζ expression were evaluated using immunohistochemistry and Western blot analysis. In the control group, PTN was mostly expressed by the EP hypertrophic chondrocytes. In groups 0 to II, PTN expression was increased in the chondrocytes of hypertrophic and proliferating zones, as well as in osteocytes and osteoblast-like cells of the ossification zone. In group III, only limited PTN expression was observed in osteocytes. RPTPß/ζ expression was increased mainly in group 0, but also in group I, in all types of cells. Low intensity RPTPß/ζ immunostaining was observed in groups II and III. Collectively, PTN and RPTPß/ζ are expressed in spinal deformities caused by mechanical loading, and their expression depends on the type and severity of the applied strain.

Chondroitin sulfate-cell membrane effectors as regulators of growth factor-mediated vascular and cancer cell migration.

BACKGROUND: Glycosylation is a multi-step post-translational enzymatic process which enhances the functional diversity of secreted or membrane proteins and is implicated in physiological and pathological conditions. Chondroitin sulfate (CS) chains are glycosaminoglycan chains, consisting of disaccharide units of glucuronic acid and N-acetylgalactosamine, attached to proteins as part of proteoglycans. SCOPE OF REVIEW: The existing knowledge on glycosylation by CS (CS glycanation) of cell membrane proteins and receptors, such as syndecans, chondroitin sulfate proteoglycan 4, betaglycan, neuropilin-1, integrins and receptor protein tyrosine phosphatase ß/ζ, is summarized and the importance of CS glycanation in growth factor-induced migration, angiogenesis and tumor growth and invasion is described. MAJOR CONCLUSIONS: Identification of glycosylation so far used to be a means of further characterizing and categorizing proteins and receptors. Although there is a significant amount of information regarding the interaction of growth factors with CS chains, very little information exists on the core proteins involved. It is now evident that there is more than meets the eye regarding the addition of glycans. GENERAL SIGNIFICANCE: Future effort should focus on characterizing CS glycanation of membrane proteins and receptors of interest in an attempt to elucidate its contribution in fine-tuning growth factor-induced signaling. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor.

BACKGROUND: Receptor protein tyrosine phosphatase beta/zeta (RPTPß/ζ) is a chondroitin sulphate (CS) transmembrane protein tyrosine phosphatase and is a receptor for pleiotrophin (PTN). RPTPß/ζ interacts with ανß3 on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Tyr530, ß3 Tyr773 phosphorylation, cell surface nucleolin (NCL) localization and stimulation of cell migration. c-Src-mediated ß3 Tyr773 phosphorylation is also observed after vascular endothelial growth factor 165 (VEGF165) stimulation of endothelial cells and is essential for VEGF receptor type 2 (VEGFR2) - ανß3 integrin association and subsequent signaling. In the present work, we studied whether RPTPß/ζ mediates angiogenic actions of VEGF. METHODS: Human umbilical vein endothelial, human glioma U87MG and stably transfected Chinese hamster ovary cells expressing different ß3 subunits were used. Protein-protein interactions were studied by a combination of immunoprecipitation/Western blot, immunofluorescence and proximity ligation assays, properly quantified as needed. RPTPß/ζ expression was down-regulated using small interference RNA technology. Migration assays were performed in 24-well microchemotaxis chambers, using uncoated polycarbonate membranes with 8 µm pores. RESULTS: RPTPß/ζ mediates VEGF165-induced c-Src-dependent ß3 Tyr773 phosphorylation, which is required for VEGFR2-ανß3 interaction and the downstream activation of phosphatidylinositol 3-kinase (PI3K) and cell surface NCL localization. RPTPß/ζ directly interacts with VEGF165, and this interaction is not affected by bevacizumab, while it is interrupted by both CS-E and PTN. Down-regulation of RPTPß/ζ by siRNA or administration of exogenous CS-E abolishes VEGF165-induced endothelial cell migration, while PTN inhibits the migratory effect of VEGF165 to the levels of its own effect. CONCLUSIONS: These data identify RPTPß/ζ as a cell membrane binding partner for VEGF that regulates angiogenic functions of endothelial cells and suggest that it warrants further validation as a potential target for development of additive or alternative anti-VEGF therapies.

Pleiotrophin-induced endothelial cell migration is regulated by xanthine oxidase-mediated generation of reactive oxygen species.

Pleiotrophin (PTN) is a heparin-binding growth factor that induces cell migration through binding to its receptor protein tyrosine phosphatase beta/zeta (RPTPß/ζ) and integrin alpha v beta 3 (ανß3). In the present work, we studied the effect of PTN on the generation of reactive oxygen species (ROS) in human endothelial cells and the involvement of ROS in PTN-induced cell migration. Exogenous PTN significantly increased ROS levels in a concentration and time-dependent manner in both human endothelial and prostate cancer cells, while knockdown of endogenous PTN expression in prostate cancer cells significantly down-regulated ROS production. Suppression of RPTPß/ζ through genetic and pharmacological approaches, or inhibition of c-src kinase activity abolished PTN-induced ROS generation. A synthetic peptide that blocks PTN-ανß3 interaction abolished PTN-induced ROS generation, suggesting that ανß3 is also involved. The latter was confirmed in CHO cells that do not express ß3 or over-express wild-type ß3 or mutant ß3Y773F/Y785F. PTN increased ROS generation in cells expressing wild-type ß3 but not in cells not expressing or expressing mutant ß3. Phosphoinositide 3-kinase (PI3K) or Erk1/2 inhibition suppressed PTN-induced ROS production, suggesting that ROS production lays down-stream of PI3K or Erk1/2 activation by PTN. Finally, ROS scavenging and xanthine oxidase inhibition completely abolished both PTN-induced ROS generation and cell migration, while NADPH oxidase inhibition had no effect. Collectively, these data suggest that xanthine oxidase-mediated ROS production is required for PTN-induced cell migration through the cell membrane functional complex of ανß3 and RPTPß/ζ and activation of c-src, PI3K and ERK1/2 kinases.

Epidermal growth factor receptor status and Notch inhibition in non-small cell lung cancer cells.

BACKGROUND: Notch may behave as an oncogene or a tumor suppressor gene in lung cancer cells. Notch receptor undergoes cleavage by enzymes, including γ-secretase, generating the active Notch intracellular domain (NICD). The aim of the present study was to investigate the effect of DAPT, a γ-secretase inhibitor, in non-small cell lung cancer (NSCLC) cells, as well as the impact of epidermal growth factor (EGF) that is over-expressed by NSCLC cells, on Notch signaling. H23, A549, H661 and HCC827 human NSCLC cell lines were used, expressing various NICD and EGF receptor (EGFR) protein levels. RESULTS: DAPT decreased the number of H661 cells in a concentration-dependent manner, while it had a small effect on H23 and A549 cells and no effect on HCC827 cells that carry mutated EGFR. Notch inhibition did not affect the stimulatory effect of EGF on cell proliferation, while EGF prevented DAPT-induced NICD decrease in H23 and H661 cells. The type of cell death induced by DAPT seems to depend on the cell type. CONCLUSIONS: Our data indicate that inhibition of Notch cleavage may not affect cell number in the presence of EGFR mutations and that EGFR may affect Notch signalling suggesting that a dual inhibition of these pathways might be promising in NSCLC.

Macrophage-specific metalloelastase (MMP-12) immunoexpression in the osteochondral unit in osteoarthritis correlates with BMI and disease severity.

BACKGROUND: Metalloproteinase 12 (MMP-12) is induced in chondrocytes during fetal development and malignant transformation. OBJECTIVES: The aim of our study is to examine the expression of MMP-12 in the cartilage and the subchondral bone of patients with osteoarthritis (OA) and to correlate its expression with disease severity and anthropometric characteristics. METHODS: Overall, 60 sections from 20 patients with idiopathic OA, were examined for the immunolocalization of MMP-12. As controls, we used the femoral heads of 4 patients treated with seniarthroplasty after fracture. Demographic characteristics and Body Mass Index (BMI) were calculated for all subjects. RESULTS: Specimens were divided into four groups based on the Mankin histological severity score. The immunohistochemical study showed MMP-12 expression in the cartilage and subchonral bone of OA patients, while there was no expression in normal controls. At the moderate OA changes (Mankin score: 6-7), MMP-12 was detected mainly at the matrix of fibrocartilage tissue. During disease progression, MMP-12 was expressed at the sides of the cartilage and bone erosion and in the bone cysts. Furthermore, it was traced in the osteocytes of the subchondral bone. Osteoblast-like cells and bone lining cells express MMP-12 during the stage of severe OA (Mankin: ≥8). Osteoclasts expressing MMP-12 were also detected in the group of severe OA. Interestingly, MMP-12 expression was positively correlated with the age and the BMI of OA patients. CONCLUSION: The increased expression of MMP-12 in the bone-cartilage unit of OA patients suggests a possible role in OA pathogenesis and progression. LEVEL OF EVIDENCE: III, prospective comparative study.

Interplay between αvß3 integrin and nucleolin regulates human endothelial and glioma cell migration.

The multifunctional protein nucleolin (NCL) is overexpressed on the surface of activated endothelial and tumor cells and mediates the stimulatory actions of several angiogenic growth factors, such as pleiotrophin (PTN). Because α(v)ß(3) integrin is also required for PTN-induced cell migration, the aim of the present work was to study the interplay between NCL and α(v)ß(3) by using biochemical, immunofluorescence, and proximity ligation assays in cells with genetically altered expression of the studied molecules. Interestingly, cell surface NCL localization was detected only in cells expressing α(v)ß(3) and depended on the phosphorylation of ß(3) at Tyr(773) through receptor protein-tyrosine phosphatase ß/ζ (RPTPß/ζ) and c-Src activation. Downstream of α(v)ß(3,) PI3K activity mediated this phenomenon and cell surface NCL was found to interact with both α(v)ß(3) and RPTPß/ζ. Positive correlation of cell surface NCL and α(v)ß(3) expression was also observed in human glioblastoma tissue arrays, and inhibition of cell migration by cell surface NCL antagonists was observed only in cells expressing α(v)ß(3). Collectively, these data suggest that both expression and ß(3) integrin phosphorylation at Tyr(773) determine the cell surface localization of NCL downstream of the RPTPß/ζ/c-Src signaling cascade and can be used as a biomarker for the use of cell surface NCL antagonists as anticancer agents.

Transauricular balloon angioplasty in rabbit thoracic aorta: a novel model of experimental restenosis.

BACKGROUND: The aim of this study was to demonstrate a percutaneous transauricular method of balloon angioplasty in high-cholesterol fed rabbits, as an innovative atherosclerosis model. METHODS: Twenty male New Zealand rabbits were randomly divided into two groups of ten animals, as follows: atherogenic diet plus balloon angioplasty (group A) and atherogenic diet alone (group B). Balloon angioplasty was performed in the descending thoracic aorta through percutaneous catheterization of the auricular artery. Eight additional animals fed regular diet were served as long term control. At the end of 9 week period, rabbits were euthanized and thoracic aortas were isolated for histological, immunohistochemical and biochemical analysis. RESULTS: Atherogenic diet induced severe hypercholesterolemia in both group A and B (2802 ± 188.59 and 4423 ± 493.39 mg/dl respectively) compared to the control animals (55.5 ± 11.82 mg/dl; P < 0.001). Group A atherosclerotic lesions appeared to be more advanced histologically (20% type IV and 80% type V) compared to group B lesions (50% type III and 50% type IV). Group A compared to group B atherosclerotic lesions demonstrated similar percentage of macrophages (79.5 ± 9.56% versus 84 ± 12.2%; P = 0.869), more smooth muscle cells (61 ± 14.10% versus 40.5 ± 17.07; P = 0.027), increased intima/media ratio (1.20 ± 0.50 versus 0.62 ± 0.13; P = 0.015) despite the similar degree of intimal hyperplasia (9768 ± 1826.79 µm² versus 12205 ± 8789.23 µm²; P = 0.796), and further significant lumen deterioration (23722 ± 4508.11 versus 41967 ± 20344.61 µm²; P = 0.05) and total vessel area reduction (42350 ± 5819.70 versus 73190 ± 38902.79 µm²; P = 0.022). Group A and B animals revealed similar nitrated protein percentage (P = NS), but significantly higher protein nitration compared to control group (P < 0.01; P < 0.01, respectively). No deaths or systemic complications were reported. CONCLUSION: Transauricular balloon angioplasty constitutes a safe, minimally invasive and highly successful model of induced atherosclerosis in hyperlipidaemic rabbits.

Bone mineral density, vitamin D and osseous metabolism indices in neurofibromatosis type 1: A systematic review and meta-analysis.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic autosomal neurocutaneous syndrome correlated with skeletal dysplasia and defects in the osseous microarchitecture. The physiological mechanism for the development of NF1-related bone abnormal turnover is still unclear. OBJECTIVES: A meta-analysis was performed to investigate the effects of NF1 on bone mineral density (BMD) and osseous metabolic indices in order to provide clinical evidence for the pathogenesis of the associated skeletal deformities. METHODS: A systematic literature review search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed/Medline and Web of Science databases from the date of inception of each database through to 10 September 2023. Specific inclusion and exclusion criteria were applied for the identification of studies examining the effects of NF1 on bone strength and metabolism. The Newcastle-Ottawa and Jadad scales were applied to assess the quality of the included studies. RevMan 5.3 software was used for the analysis of the data, and MedCalc was applied to examine publication bias. RESULTS: Overall, 13 studies met the inclusion criteria comprised of 5 cross-sectional, 6 case-control and 2 retrospective studies. 703 patients and 973 healthy subjects formed the NF1 and control group, respectively. The results of the meta-analysis displayed that lumbar (SMD = -3.85, 95%CI = -7.53 to -0.18, Z = 2.05, p = 0.04) and femoral (SMD = -4.78, 95%CI = -8.86 to -0.69, Z = 2.29, p = 0.02) BMD was reduced in the NF1 group. Both in children and adults the serum levels of 25 hydroxyvitamin D3 were also decreased in NF1 group, but without any statistical significance (SMD = -0.62, 95%CI = -1.34 to -0.11, Z = 1.66, p = 0.10). Serum Parathyroid hormone (PTH) (SMD = 0.73, 95%CI = 0.31 to 1.15, Z = 3.43, p = 0.0006) and C-telopeptide of type 1 collagen (CTX) (SMD = 0.82, 95%CI = 0.33 to 1.30, Z = 3.29, p = 0.001) were elevated in NF1 patients, while serum calcium (SMD = -0.10, 95%CI = -0.74 to 0.53, Z = 0.32, p = 0.75) phosphorous (SMD = 0.33, 95%CI = -0.38 to 1.05, Z = 0.92, p = 0.36), alkaline phosphatase (ALP) (SMD = -0.36, 95%CI = -0.77 to 0.05, Z = 1.71, p = 0.09), osteocalcin (SMD = 1.81, 95%CI = -0.37 to -3.98, Z = 1.63, p = 0.10) and bone formation markers (SMD = 0.28, 95%CI = -0.37 to -0.94, Z = 0.85, p = 0.39) were not. CONCLUSION: NF1 is associated with decreased BMD at the lumbar spine and femur. Taking into account that the serum levels of PTH, CTX were increased whereas the concentrations of vitamin D, calcium, phosphorous, ALP, osteocalcin and bone formation markers were not altered significantly in the NF1 patients compared with the healthy subjects, a vitamin D independent dysregulated bone cellular activity could be considered. STUDY REGISTRATION: Registered on PROSPERO (CRD42023424751).

Unraveling the Link of Altered TGFß Signaling with Scoliotic Vertebral Malformations in Osteogenesis Imperfecta: A Comprehensive Review.

Osteogenesis Imperfecta (OI) is a genetic disorder caused by mutations in genes responsible for collagen synthesis or polypeptides involved in the formation of collagen fibers. Its predominant skeletal complication is scoliosis, impacting 25 to 80% of OI patients. Vertebral deformities of the scoliotic curves in OI include a variety of malformations such as codfish, wedged-shaped vertebrae or platyspondyly, craniocervical junction abnormalities, and lumbosacral spondylolysis and spondylolisthesis. Although the precise pathophysiology of these spinal deformities remains unclear, anomalies in bone metabolism have been implicated in the progression of scoliotic curves. Bone Mineral Density (BMD) measurements have demonstrated a significant reduction in the Z-score, indicating osteoporosis and a correlation with the advancement of scoliosis. Factors such as increased mechanical strains, joint hypermobility, lower leg length discrepancy, pelvic obliquity, spinal ligament hypermobility, or vertebrae microfractures may also contribute to the severity of scoliosis. Histological vertebral analysis has confirmed that changes in trabecular microarchitecture, associated with inadequate bone turnover, indicate generalized bone metabolic defects in OI. At the molecular level, the upregulation of Transforming Growth factor-ß (TGFß) signaling in OI can lead to disturbed bone turnover and changes in muscle mass and strength. Understanding the relationship between spinal clinical features and molecular pathways could unveil TGFß -related molecular targets, paving the way for novel therapeutic approaches in OI.

Targeting the interaction of pleiotrophin and VEGFA165 with protein tyrosine phosphatase receptor zeta 1 inhibits endothelial cell activation and angiogenesis.

Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) that serves as a receptor for pleiotrophin (PTN) and vascular endothelial growth factor A 165 (VEGFA165) to regulate endothelial cell migration. In the present work, we identify a PTN peptide fragment (PTN97-110) that inhibits the interaction of PTN and VEGFA165 with PTPRZ1 but not VEGF receptor 2. This peptide abolishes the stimulatory effect of PTN and VEGFA165 on endothelial cell migration, tube formation on Matrigel, and Akt activation in vitro. It also partially inhibits VEGFA165-induced VEGF receptor 2 activation but does not affect ERK1/2 activation and cell proliferation. In vivo, PTN97-110 inhibits or dysregulates angiogenesis in the chick embryo chorioallantoic membrane and the zebrafish assays, respectively. In glioblastoma cells in vitro, PTN97-110 abolishes the stimulatory effect of VEGFA165 on cell migration and inhibits their anchorage-independent growth, suggesting that this peptide might also be exploited in glioblastoma therapy. Finally, in silico and experimental evidence indicates that PTN and VEGFA165 bind to the extracellular fibronectin type-III (FNIII) domain to stimulate cell migration. Collectively, our data highlight novel aspects of the interaction of PTN and VEGFA165 with PTPRZ1, strengthen the notion that PTPRZ1 is required for VEGFA165-induced signaling, and identify a peptide that targets this interaction and can be exploited for the design of novel anti-angiogenic and anti-glioblastoma therapeutic approaches.

Subchondral Bone Cyst Development in Osteoarthritis: From Pathophysiology to Bone Microarchitecture Changes and Clinical Implementations.

Osteoarthritis is a degenerative joint disease affecting middle-aged and elderly patients. It mainly involves weight-bearing joints such as the hip, knee and spine as well as the basilar joint of the thumb, causing dysfunction and painful symptoms. Often, joint arthritis is accompanied by cartilage defects, joint space narrowing, osteophytes, bone sclerosis and subchondral bone cysts (SBC). The aim of the present study was to explore the pathophysiology responsible for the development of SBCs as well as the association between SBCs and disease progress, the level of clinical symptoms and their impact on postoperative outcomes and risk of possible complications following joint replacements if left untreated. A literature review on PubMed articles was conducted to retrieve and evaluate all available evidence related to the main objective mentioned above. A few theories have been put forth to explain the formation process of SBCs. These involve MMPs secretion, angiogenesis, and enhanced bone turnover as a biological response to abnormal mechanical loads causing repeated injuries on cartilage and subchondral tissue during the development of arthritis. However, the application of novel therapeutics, celecoxib-coated microspheres, local administration of IGF-1 and activated chondrocytes following surgical debridement of SBCs hinders the expansion of SBCs and prevents the progression of osteoarthritis.