Mutations in fibronectin dysregulate chondrogenesis in skeletal dysplasia

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Fibronectin (FN) is vital for vertebrate organ development.
• Mutations in FN cause spondylometaphyseal dysplasia (SMDCF), a skeletal disorder.
• The cellular mechanisms of FN-related skeletal dysplasia are not fully understood.

Purpose of the Study:

• To investigate the impact of FN mutations on mesenchymal stem cells (MSCs) and chondrogenesis in SMDCF.
• To elucidate the molecular pathways underlying skeletal development defects in SMDCF.

Main Methods:

• Generated patient-derived induced pluripotent stem cells (iPSCs) as an SMDCF model.
• Analyzed protein secretion, intracellular/extracellular FN levels, and cellular stress markers in MSCs.
• Performed bulk RNA sequencing and assessed MSC differentiation into chondrocytes.
• Investigated the effects of exogenous FN and TGFβ1 supplementation.

Main Results:

• FN mutations impaired protein secretion, increasing intracellular FN and decreasing extracellular FN.
• Accumulation of FN and ER chaperones in cytosolic vesicles led to cellular stress and mitochondrial dysfunction.
• Mutant MSCs showed impaired chondrogenesis, reduced TGFβ1 expression, and compromised proliferation.
• Exogenous FN or TGFβ1 supplementation rescued chondrogenesis defects.

Conclusions:

• FN mutations disrupt protein homeostasis and cellular function in MSCs.
• Altered chondrogenesis and reduced TGFβ1 are key mechanisms in FN-related skeletal dysplasia.
• Targeting FN and TGFβ1 pathways offers potential therapeutic strategies for SMDCF.