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

// Camilla Evangelisti 1 , Pia Bernasconi 2 , Paola Cavalcante 2 , Cristina Cappelletti 2 , Maria Rosaria D’Apice 3 , Paolo Sbraccia 4 , Giuseppe Novelli 5 , Sabino Prencipe 1 , Silvia Lemma 6 , Nicola Baldini 6 , Sofia Avnet 6 , Stefano Squarzoni 1 , Alberto M. Martelli 7 , Giovanna Lattanzi 1 1 Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy 2 Neurology IV Unit - Neuroimmunology and Neuromuscular Disorders, Foundation IRCCS Neurological Institute “Carlo Besta”, Milan, Italy 3 U.O.C. Medical Genetics Laboratory, AOU Policlinico Tor Vergata, Rome, Italy 4 Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy 5 Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy 6 Rizzoli Orthopedic Institute, Laboratory for Pathophysiology, Bologna, Italy 7 Department 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.