Characterization of dynamic changes in Matrix Gla Protein (MGP) gene expression as function of genetic risk alleles, osteoarthritis relevant stimuli, and the vitamin K inhibitor warfarin.

Abstract

OBJECTIVE:

We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin.

METHODS:

Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1β; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes.

RESULTS:

We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression.

DISCUSSION & CONCLUSIONS:

Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in cartilage. The determined direct negative effect of warfarin on human explant cultures functionally underscores the previously found association between vitamin K deficiency and OA.

• Authors: E Houtman, R Coutinho de Almeida, M Tuerlings, H E D Suchiman, D Broekhuis, R G H H Nelissen, Y F M Ramos, J B J van Meurs, I Meulenbelt
• Journal: Osteoarthritis and cartilage (Osteoarthritis Cartilage) Vol. 29 Issue 8 Pg. 1193-1202 (08 2021) ISSN: 1522-9653 [Electronic] England
• PMID: 33984465 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• COL10A1 protein, human
• COL1A1 protein, human
• Calcium-Binding Proteins
• Cell Adhesion Molecules
• Collagen Type I, alpha 1 Chain
• Collagen Type X
• Extracellular Matrix Proteins
• POSTN protein, human
• RNA, Messenger
• SOX9 Transcription Factor
• SOX9 protein, human
• matrix Gla protein
• Vitamin K
• Warfarin
• MMP3 protein, human
• Matrix Metalloproteinase 3

Topics

• Alleles
• Calcium-Binding Proteins (genetics, metabolism)
• Cartilage, Articular (metabolism)
• Cell Adhesion Molecules (metabolism)
• Collagen Type I, alpha 1 Chain (metabolism)
• Collagen Type X (metabolism)
• Down-Regulation
• Extracellular Matrix Proteins (genetics, metabolism)
• Gene Expression
• Humans
• Matrix Metalloproteinase 3 (metabolism)
• Osteoarthritis (genetics, metabolism)
• RNA, Messenger (metabolism)
• SOX9 Transcription Factor (metabolism)
• Up-Regulation
• Vitamin K (antagonists & inhibitors)
• Warfarin (pharmacokinetics, pharmacology)