Lamins and bone disorders: current understanding and perspectives

// Chiara Gargiuli 1 , Elisa Schena 1, 2 , Elisabetta Mattioli 1, 2 , Marta Columbaro 2 , Maria Rosaria D'Apice 3 , Giuseppe Novelli 3 , Tiziana Greggi 4 and Giovanna Lattanzi 1, 2 1 CNR Institute of Molecular Genetics, Unit of Bologna, Bologna, Italy 2 Rizzoli Orthopaedic Institute, Laboratory of Cell Biology, Bologna, Italy 3 Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Rome, Italy 4 Rizzoli Orthopaedic Institute, Spine Deformity Department, Bologna, Italy Correspondence to: Giovanna Lattanzi, email: lattanzi@area.bo.cnr.it Chiara Gargiuli, email: chiara.ga13@alice.it Keywords: lamin A/C; LMNA-related congenital muscular dystrophy (L-CMD); hutchinson-gilford progeria syndrome (HGPS); mandibuloacral dysplasia (MADA, MADB); bone turnover Received: October 11, 2017      Accepted: March 22, 2018      Published: April 27, 2018 ABSTRACT Lamin A/C is a major constituent of the nuclear lamina implicated in a number of genetic diseases, collectively known as laminopathies. The most severe forms of laminopathies feature, among other symptoms, congenital scoliosis, osteoporosis, osteolysis or delayed cranial ossification. Importantly, specific bone districts are typically affected in laminopathies. Spine is severely affected in LMNA-linked congenital muscular dystrophy. Mandible, terminal phalanges and clavicles undergo osteolytic processes in progeroid laminopathies and Restrictive Dermopathy, a lethal developmental laminopathy. This specificity suggests that lamin A/C regulates fine mechanisms of bone turnover, as supported by data showing that lamin A/C mutations activate non-canonical pathways of osteoclastogenesis, as the one dependent on TGF beta 2. Here, we review current knowledge on laminopathies affecting bone and LMNA involvement in bone turnover and highlight lamin-dependent mechanisms causing bone disorders. This knowledge can be exploited to identify new therapeutic approaches not only for laminopathies, but also for other rare diseases featuring bone abnormalities.