title: Modulation of TGFbeta 2 levels by lamin A in U2-OS osteoblast-like cells: understanding the osteolytic process triggered by altered lamins.
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.
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Neurology IV Unit - Neuroimmunology and Neuromuscular Disorders, Foundation IRCCS Neurological Institute "Carlo Besta", Milan, Italy.
authors.forename: Pia
authors.initials: P
authors.lastname: Bernasconi
authors.affiliation: Neurology IV Unit - Neuroimmunology and Neuromuscular Disorders, Foundation IRCCS Neurological Institute "Carlo Besta", Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cavalcante
authors.affiliation: Neurology IV Unit - Neuroimmunology and Neuromuscular Disorders, Foundation IRCCS Neurological Institute "Carlo Besta", Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cappelletti
authors.affiliation: U.O.C. Medical Genetics Laboratory, AOU Policlinico Tor Vergata, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.affiliation: Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sbraccia
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy.
authors.forename: Sabino
authors.initials: S
authors.lastname: Prencipe
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory for Pathophysiology, Bologna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lemma
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory for Pathophysiology, Bologna, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory for Pathophysiology, Bologna, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Squarzoni
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D000068338:Everolimus / Q000494:pharmacology; D006801:Humans; D034904:Lamin Type A / Q000096:biosynthesis / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D053781:Transforming Growth Factor beta2; C090764:prelamin A; D000068338:Everolimus; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt signaling; RAD001; TGFbeta2; lamin A; osteoclasts
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