title: Bone morphogenetic protein 4 and its receptors are expressed in the leptomeninges and meningiomas and signal via the Smad pathway.
abstract: The roles of bone morphogenetic proteins (BMPs) and their receptors (BMPRs) in meningioma biology are not known. In this study, frozen tissues from 26 World Health Organization Grades I to III meningiomas were analyzed by Western blot for BMP-2/4, BMPR IA, and BMPR II, and activation of downstream p-Smad1, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling molecules. Sections from 20 normal leptomeninges, 2 arachnoid cysts, and 51 meningiomas were analyzed for BMP-4 and p44/42 MAPK by immunohistochemistry. Primary meningioma cultures from 11 meningiomas were treated with BMP-4 and evaluated for cell proliferation and signaling pathway activation. Conditioned media from 7 cultures were analyzed for BMP-4 by ELISA. Bone morphogenetic protein 4 was variably detected in adult leptomeninges but was detected in 89% or 84% of Grade I meningiomas and in 60% of Grade II meningiomas by Western blot and immunohistochemistry, respectively. Bone morphogenetic protein receptors IA and II were detected in leptomeninges and in all meningiomas studied, and activated Smad1 was detected in all meningiomas studied. Bone morphogenetic protein 4 stimulated meningioma cell proliferation and phosphorylation/activation of Smad1 but not p38 MAPK or p44/42 MAPK in vitro, and it was detected in conditioned media from 4 of 7 cultures. These findings suggest that BMP-4 and BMPRs may play autocrine/paracrine roles and interact with other transforming growth factor-beta superfamily members in regulating meningioma growth and differentiation.
authors.affiliation: Department of Pathology, Division of Neuropathology and Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, USA. mahlon_johnson@urmc.rochester.edu
authors.forename: Mahlon D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Mary J
authors.initials: MJ
authors.lastname: O'Connell
authors.forename: Fran
authors.initials: F
authors.lastname: Vito
authors.forename: Webster
authors.initials: W
authors.lastname: Pilcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis* / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000378:metabolism* / Q000473:pathology; D008579:Meningioma / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D055415:Bone Morphogenetic Protein 4; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D052006:Bone Morphogenetic Protein Receptors, Type II