Cytokine signaling in laminopathies: focus on TGFbeta 2

An increasing number of studies in human and mouse models of laminopathies highlight dysregulation of cytokine levels downstream of lamin mutations. Moreover, involvement of cytokines has been suggested in inflammatory and non-inflammatory muscle diseases. These considerations prompted us to set up a wide screening of cytokine regulation in Italian patients affected by diverse laminopathies. In sera collected from a large cohort of individuals affected by Emery-Dreifuss Muscular Dystrophy, Limb-Girdle Muscular Dystrophy 1B, Dilated Cardiomyopathy with conduction system disease, type 2 Familial Partial Lipodystrophy, Mandibuloacral Dysplasia, Atypical Progeria Syndrome, we found an interesting effect of lamin mutations on a few cytokines including IL17, IL6, VEGF and TGFbetas. Some of these results were consistent with data obtained in laminopathic primary cell cultures. The biological effects of TGFbeta 2 were tested in cellular models of bone, muscle and adipocyte differentiation to unravel potential pathogenetic mechanisms. Moreover, the signaling effectors of lamin-dependent TGFbeta2 pathways were identified. The results pave the way to further investigation in animal models and suggest biomarkers and therapeutic targets for laminopathies.