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

• DOI: 10.18632/oncotarget.3232
• Publication Date: 2015-09-15T07:54:05Z
• Authors: Camilla Evangelisti; Pia Bernasconi; Paola Cavalcante; Cristina Cappelletti; Maria Rosaria D’A...; Paolo Sbraccia; Giuseppe Novelli; Sabino Prencipe; Silvia Lemma; Nicola Baldini; Sofia Avnet; Stefano Squarzoni; Alberto M. Martelli; Giovanna Lattanzi
• Keywords: LMNA; Follistatin

// Camilla Evangelisti 1 , Pia Bernasconi 2 Paola Cavalcante Cristina Cappelletti Maria Rosaria D'Apice 3 Paolo Sbraccia 4 Giuseppe Novelli 5 Sabino Prencipe Silvia Lemma 6 Nicola Baldini Sofia Avnet Stefano Squarzoni Alberto M. Martelli 7 Giovanna Lattanzi Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, CNR Institute for Molecular Genetics, Unit Bologna, Italy Neurology IV - Neuroimmunology and Neuromuscular Disorders, Foundation IRCCS Neurological "Carlo Besta", Milan, U.O.C. Medical Genetics Laboratory, AOU Policlinico Tor Vergata, Rome, Department Internal Medicine, University Rome Biomedicine Prevention, Pathophysiology, Biomedical Neuromotor Sciences, Correspondence to: Lattanzi, e-mail: [e-mail] Evangelisti, [e-mail] Keywords: TGFbeta2, lamin A, osteoclasts, Akt signaling, RAD001 Received: January 19, 2015 Accepted: 28, Published: March 16, ABSTRACT Transforming growth factor beta (TGFbeta) plays an essential role in bone homeostasis deregulation TGFbeta occurs pathologies. Patients affected by Mandibuloacral Dysplasia (MADA), a progeroid disease linked to LMNA mutations, suffer from osteolytic process. Our previous work showed that MADA osteoblasts secrete excess amount 2, which turn elicits differentiation human blood precursors into osteoclasts. Here, we sought determine how altered A affects signaling. results show wild-type negatively modulates levels osteoblast-like U2-OS cells, while the R527H mutated prelamin as well farnesylated do not, ultimately leading increased secretion 2. turn, triggers Akt/mTOR pathway upregulates osteoprotegerin cathepsin K. neutralization rescues activation downstream transcriptional effects, effect also obtained statins or treatment. unravel unexpected regulation indicate rapamycin analogs neutralizing antibodies new potential therapeutic tools MADA.