Combined ADAMTS10 and ADAMTS17 inactivation exacerbates bone shortening and compromises extracellular matrix...

Area of Science:

• Biochemistry
• Genetics
• Developmental Biology

Background:

• Weill-Marchesani syndrome (WMS) is a genetic disorder affecting connective tissues, characterized by short stature and skeletal anomalies.
• Mutations in ADAMTS10, ADAMTS17, or LTBP2 cause recessive WMS, while FBN1 mutations cause dominant WMS.
• The involvement of these extracellular matrix (ECM) proteins suggests a shared pathway regulating chondrocyte function and growth plate development.

Purpose of the Study:

• To investigate the roles of ADAMTS proteases ADAMTS10 and ADAMTS17 in growth plate function and ECM formation.
• To elucidate the molecular mechanisms by which these proteases influence skeletal development.

Main Methods:

• Generation and analysis of Adamts10;Adamts17 double knockout (DKO) mice.
• Assessment of skeletal phenotypes, including bone length and growth plate morphology.
• Identification of ADAMTS17 substrates using N-terminomics and yeast two-hybrid screening.
• Analysis of ECM deposition in primary skin fibroblasts from deficient mice.

Main Results:

• Adamts10;Adamts17 DKO mice exhibited significant postnatal lethality and severe bone shortening with narrower growth plate hypertrophic zones.
• ADAMTS17 was implicated in ECM protein secretion and assembly, with fibronectin deposition compromised and fibrillin-1 accumulating intracellularly in deficient fibroblasts.
• While fibronectin and collagen VI were identified as potential ADAMTS17 substrates, direct proteolysis was not confirmed.

Conclusions:

• ADAMTS10 and ADAMTS17 are essential regulators of bone growth, impacting chondrocyte hypertrophy and turnover.
• ADAMTS17 plays a critical role in ECM protein secretion and pericellular matrix assembly.
• ADAMTS10 likely influences ECM formation at later stages, potentially affecting fibrillin isoform deposition.