Osteoblasts from a mandibuloacral dysplasia patient induce human blood precursors to differentiate into active osteoclasts

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1812

Article

Avnet, Sofia²  Pallotta, Rosanna³  Perut, Francesca²  Baldini, Nicola²  Pittis, Maria Gabriela⁴  Saponari, Anita³  Lucarelli, Enrico⁵  Dozza, Barbara⁵  Greggi, Tiziana⁶  Maraldi, Nadir M.⁷  Columbaro, Marta⁷  Lattanzi, Giovanna¹ 

[1] IGM CNR, Inst Mol Genet, Unit Bologna, IOR, I-40136 Bologna, Italy

[2] Ist Ortoped Rizzoli, Lab Pathophysiol, Bologna, Italy

[3] Univ G DAnnunzio, Clin Genet Dept Med & Aging Sci, Chieti, Italy

[4] Univ Hosp, Rare Dis Coordinat Ctr, Udine, Italy

[5] Ist Ortoped Rizzoli, Bone Regenerat Lab, Bologna, Italy

[6] Ist Ortoped Rizzoli, Spinal Deform Surg Dept, Bologna, Italy

[7] Ist Ortoped Rizzoli, Lab Musculoskeletal Cell Biol RAMSES, Bologna, Italy

关键词: Mandibuloacral dysplasia;    Lamin A/C;    Osteoblast;    Osteoclast;    Osteoprotegerin;    TGFbeta 2;   

DOI  :  10.1016/j.bbadis.2011.03.006

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier B.V. All rights reserved.

【 授权许可】

Free