Elevated MMP9 Expression-A Potential In Vitro Biomarker for COMPopathies

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Intracellular retention of misfolded proteins is a key mechanism in rare skeletal diseases.
• Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are therapeutic targets for skeletal dysplasias.
• Current treatments like carbamazepine are ineffective for some skeletal disorders, highlighting the need for better diagnostic markers.

Purpose of the Study:

• To identify a common in vitro marker for COMPopathies, a group of skeletal dysplasias caused by mutations in cartilage oligomeric matrix protein (COMP).
• To investigate the role of ER stress and UPR in COMPopathies.
• To differentiate COMPopathies from other skeletal disorders with similar disease mechanisms.

Main Methods:

• Utilized cell models of COMPopathies.
• Analyzed gene expression patterns, specifically focusing on MMP9.
• Investigated the induction of ER stress and UPR in response to COMP mutations.

Main Results:

• Identified MMP9 upregulation as a common feature in cell models of six pathogenic COMP variants.
• Demonstrated that these MMP9-upregulating COMP variants do not induce a prominent UPR.
• Showed that a specific MED variant (p.V194D matrilin-3) does not induce MMP9 expression, suggesting specificity.

Conclusions:

• MMP9 upregulation serves as a specific in vitro marker for COMPopathies.
• This marker is particularly useful for COMP variants that do not elicit a strong UPR.
• The findings pave the way for improved in vitro drug screening for COMPopathies.