| First Author | Sedes L | Year | 2022 |
| Journal | Hum Mol Genet | Volume | 31 |
| Issue | 19 | Pages | 3281-3289 |
| PubMed ID | 35567544 | Mgi Jnum | J:353715 |
| Mgi Id | MGI:7444607 | Doi | 10.1093/hmg/ddac107 |
| Citation | Sedes L, et al. (2022) Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome. Hum Mol Genet 31(19):3281-3289 |
| abstractText | A disproportionate tall stature is the most evident manifestation in Marfan syndrome (MFS), a multisystem condition caused by mutations in the extracellular protein and TGFbeta modulator, fibrillin-1. Unlike cardiovascular manifestations, there has been little effort devoted to unravel the molecular mechanism responsible for long bone overgrowth in MFS. By combining the Cre-LoxP recombination system with metatarsal bone cultures, here we identify the outer layer of the perichondrium as the tissue responsible for long bone overgrowth in MFS mice. Analyses of differentially expressed genes in the fibrillin-1-deficient perichondrium predicted that loss of TGFbeta signaling may influence chondrogenesis in the neighboring epiphyseal growth plate (GP). Immunohistochemistry revealed that fibrillin-1 deficiency in the outer perichondrium is associated with decreased accumulation of latent TGFbeta-binding proteins (LTBPs)-3 and -4, and reduced levels of phosphorylated (activated) Smad2. Consistent with these findings, mutant metatarsal bones grown in vitro were longer and released less TGFbeta than the wild-type counterparts. Moreover, addition of recombinant TGFbeta1 normalized linear growth of mutant metatarsal bones. We conclude that longitudinal bone overgrowth in MFS is accounted for by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix of the outer perichondrium, which results in less TGFbeta signaling locally and improper GP differentiation distally. |
