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Elevated MMP9 Expression-A Potential In Vitro Biomarker for COMPopathies.

Helen F Dietmar1, Ella P Dennis1, Francesca M Johnson de Sousa Brito1

  • 1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

International Journal of Molecular Sciences
|December 30, 2025
PubMed
Summary
This summary is machine-generated.

Misfolded proteins cause rare skeletal diseases. Researchers identified MMP9 upregulation as a specific marker for COMPopathies, aiding in vitro drug screening for these conditions.

Keywords:
biomarkerendoplasmic reticulum/cell stressmatrix metalloproteinaseprotein misfoldingskeletal dysplasia

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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.