Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Modulation of TGFbeta 2 levels by lamin A in U2-OS osteoblast-like cells: understanding the osteolytic process triggered by altered lamins

Camilla Evangelisti _, Pia Bernasconi, Paola Cavalcante, Cristina Cappelletti, Maria Rosaria D’Apice, Paolo Sbraccia, Giuseppe Novelli, Sabino Prencipe, Silvia Lemma, Nicola Baldini, Sofia Avnet, Stefano Squarzoni, Alberto M. Martelli and Giovanna Lattanzi

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Oncotarget. 2015; 6:7424-7437. https://doi.org/10.18632/oncotarget.3232

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Abstract

Camilla Evangelisti1, Pia Bernasconi2, Paola Cavalcante2, Cristina Cappelletti2, Maria Rosaria D’Apice3, Paolo Sbraccia4, Giuseppe Novelli5, Sabino Prencipe1, Silvia Lemma6, Nicola Baldini6, Sofia Avnet6, Stefano Squarzoni1, Alberto M. Martelli7, Giovanna Lattanzi1

1Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy

2Neurology IV Unit - Neuroimmunology and Neuromuscular Disorders, Foundation IRCCS Neurological Institute “Carlo Besta”, Milan, Italy

3U.O.C. Medical Genetics Laboratory, AOU Policlinico Tor Vergata, Rome, Italy

4Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy

5Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

6Rizzoli Orthopedic Institute, Laboratory for Pathophysiology, Bologna, Italy

7Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

Correspondence to:

Giovanna Lattanzi, e-mail: lattanzi@area.bo.cnr.it

Camilla Evangelisti, e-mail: camilla.evangelisti@gmail.com

Keywords: TGFbeta2, lamin A, osteoclasts, Akt signaling, RAD001

Received: January 19, 2015     Accepted: January 28, 2015     Published: March 16, 2015

ABSTRACT

Transforming growth factor beta (TGFbeta) plays an essential role in bone homeostasis and deregulation of TGFbeta occurs in bone pathologies. Patients affected by Mandibuloacral Dysplasia (MADA), a progeroid disease linked to LMNA mutations, suffer from an osteolytic process. Our previous work showed that MADA osteoblasts secrete excess amount of TGFbeta 2, which in turn elicits differentiation of human blood precursors into osteoclasts. Here, we sought to determine how altered lamin A affects TGFbeta signaling. Our results show that wild-type lamin A negatively modulates TGFbeta 2 levels in osteoblast-like U2-OS cells, while the R527H mutated prelamin A as well as farnesylated prelamin A do not, ultimately leading to increased secretion of TGFbeta 2. TGFbeta 2 in turn, triggers the Akt/mTOR pathway and upregulates osteoprotegerin and cathepsin K. TGFbeta 2 neutralization rescues Akt/mTOR activation and the downstream transcriptional effects, an effect also obtained by statins or RAD001 treatment. Our results unravel an unexpected role of lamin A in TGFbeta 2 regulation and indicate rapamycin analogs and neutralizing antibodies to TGFbeta 2 as new potential therapeutic tools for MADA.


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