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Laser Capture Microdissection of Mouse Embryonic Cartilage and Bone for Gene Expression Analysis
Published on: December 18, 2019
Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome
Lauriane Sedes1, Elisa Wondimu1, Brittany Crockett1
1Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10021, USA.
Abstract:
A disproportionate tall stature is the most evident manifestation in Marfan syndrome (MFS), a multisystem condition caused by mutations in the extracellular protein and TGFβ 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 TGFβ 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 TGFβ-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 TGFβ than the wild-type counterparts. Moreover, addition of recombinant TGFβ1 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 TGFβ signaling locally and improper GP differentiation distally.
Insights
Marfan syndrome (MFS) causes tall stature due to fibrillin-1 mutations. This study reveals the outer perichondrium drives long bone overgrowth by altering TGFβ signaling, impacting growth plate differentiation.
Area of Science:
- Genetics and Molecular Biology
- Skeletal Biology
- Connective Tissue Disorders
Background:
- Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, primarily known for causing disproportionate tall stature.
- Mutations in the fibrillin-1 gene are the main cause of MFS, impacting the extracellular matrix and transforming growth factor beta (TGFβ) signaling.
- The molecular mechanisms underlying long bone overgrowth in MFS remain poorly understood, unlike its cardiovascular manifestations.
Purpose of the Study:
- To identify the specific tissue responsible for long bone overgrowth in Marfan syndrome.
- To elucidate the molecular mechanisms involving fibrillin-1, TGFβ signaling, and chondrogenesis in MFS-related bone elongation.
- To investigate the role of latent TGFβ-binding proteins (LTBPs) in MFS bone growth.
Main Methods:
- Utilized the Cre-LoxP recombination system in mice to study fibrillin-1 deficiency.
- Employed metatarsal bone cultures to analyze long bone growth in vitro.
- Performed gene expression analysis and immunohistochemistry on perichondrium and growth plate tissues.
- Measured TGFβ release from cultured bones and assessed the effect of recombinant TGFβ1.
Main Results:
- Identified the outer perichondrium as the primary site responsible for long bone overgrowth in MFS mouse models.
- Demonstrated decreased accumulation of LTBP-3 and LTBP-4 in the fibrillin-1-deficient perichondrium.
- Observed reduced levels of activated Smad2, indicating diminished TGFβ signaling in MFS perichondrium.
- Mutant metatarsal bones exhibited increased length and reduced TGFβ release in vitro, which was normalized by exogenous TGFβ1.
Conclusions:
- Longitudinal bone overgrowth in MFS is attributed to impaired LTBP-3 and LTBP-4 sequestration in the fibrillin-1-deficient outer perichondrium.
- This deficiency leads to reduced local TGFβ signaling, consequently affecting differentiation in the epiphyseal growth plate.
- Targeting TGFβ signaling pathways presents a potential therapeutic strategy for managing bone overgrowth in Marfan syndrome.
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