title: Osteoblasts from a mandibuloacral dysplasia patient induce human blood precursors to differentiate into active osteoclasts.
abstract: Mandibuloacral dysplasia type A (MADA) is a rare disease caused by mutations in the LMNA gene encoding A type lamins. Patients affected by mandibuloacral dysplasia type A suffer from partial lipodystrophy, skin abnormalities and accelerated aging. Typical of mandibuloacral dysplasia type A is also bone resorption at defined districts including terminal phalanges, mandible and clavicles. Little is known about the biological mechanism underlying osteolysis in mandibuloacral dysplasia type A. In the reported study, we analyzed an osteoblast primary culture derived from the cervical vertebrae of a mandibuloacral dysplasia type A patient bearing the homozygous R527H LMNA mutation. Mandibuloacral dysplasia type A osteoblasts showed nuclear abnormalities typical of laminopathic cells, but they proliferated in culture and underwent differentiation upon stimulation with dexamethasone and beta-glycerophosphate. Differentiated osteoblasts showed proper production of bone mineral matrix until passage 8 in culture, suggesting a good differentiation activity. In order to evaluate whether mandibuloacral dysplasia type A osteoblast-derived factors affected osteoclast differentiation or activity, we used a conditioned medium from mandibuloacral dysplasia type A or control cultures to treat normal human peripheral blood monocytes and investigated whether they were induced to differentiate into osteoclasts. A higher osteoclast differentiation and matrix digestion rate was obtained in the presence of mandibuloacral dysplasia type A osteoblast medium with respect to normal osteoblast medium. Further, TGFbeta 2 and osteoprotegerin expression were enhanced in mandibuloacral dysplasia type A osteoblasts while the RANKL/osteoprotegerin ratio was diminished. Importantly, inhibition of TGFbeta 2 by a neutralizing antibody abolished the effect of mandibuloacral dysplasia type A conditioned medium on osteoclast differentiation. These data argue in favor of an altered bone turnover in mandibuloacral dysplasia type A, caused by upregulation of bone-derived stimulatory cytokines, which activate non-canonical differentiation stimuli. In this context, TGFbeta 2 appears as a major player in the osteolytic process that affects mandibuloacral dysplasia type A patients.
authors.affiliation: Laboratory for Pathophysiology, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pallotta
authors.forename: Francesca
authors.initials: F
authors.lastname: Perut
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
authors.forename: Maria Gabriela
authors.initials: MG
authors.lastname: Pittis
authors.forename: Anita
authors.initials: A
authors.lastname: Saponari
authors.forename: Enrico
authors.initials: E
authors.lastname: Lucarelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Dozza
authors.forename: Tiziana
authors.initials: T
authors.lastname: Greggi
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.forename: Cristina
authors.initials: C
authors.lastname: Capanni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattioli
authors.forename: Marta
authors.initials: M
authors.lastname: Columbaro
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
mesh_terms: D030981:Acro-Osteolysis / Q000097:blood / Q000473:pathology*; D000469:Alkaline Phosphatase / Q000378:metabolism; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D008854:Microscopy, Electron; D010006:Osteoblasts / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology*
chemical_list: D017931:DNA Primers; D000469:Alkaline Phosphatase