# Role of MMPs in arterial calcification

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $463,538

## Abstract

Project summary/abstract
Arterial calcification has increasingly been associated with poor outcomes in a wide variety of patient
populations including those with coronary, aortic, and peripheral artery disease, as well as patients with
diabetes, and renal failure. We previously demonstrated that calcification in peripheral arteries predicts major
amputation even after adjusting for demographics, cardiovascular risk factors, and the ankle brachial index.
During arterial calcification, medial smooth muscle cells (SMCs) undergo osteogenic transformation with loss
of phenotype-specific markers and new expression of factors and signaling molecules most commonly found in
developing bone. We and others have established a critical role for matrix metalloproteinases (MMPs) in the
progression of arterial calcification. MMPs are highly expressed in calcifying arteries, and we have
demonstrated that reducing their activity with broad spectrum and synthetic inhibitors can prevent experimental
calcification both in vitro and in vivo. In preliminary data for the current proposal, we show that MMP-3
(stromelysin-1) is the most strongly induced of all metalloproteinases in calcifying rodent aortas. Reducing
MMP-3 activity decreases calcium accumulation in cultured human and rodent SMCs and in a rat aorta organ
culture model. Aortas from MMP-3-deficient mice are protected from medial calcification in organ culture and in
vivo. Additionally, we have recently shown that MMP-3 can decrease levels of ENPP1 that generates anti-
calcifying pyrophosphate (PPi) from ATP. The location of MMP-3 activity required for calcification, whether
local or systemic, and its contribution to SMC transformation is not currently known and this may act as a
barrier to development of appropriate inhibitors for use in clinical trials. Based on our data and those of others,
we propose the overarching hypothesis that MMP-3 contributes to medial artery calcification by promoting
transformation of vascular SMCs and altering the balance of circulating stimulators and inhibitors. Reducing
MMP-3 activity will slow the progression of arterial calcification in patients. As we test this hypothesis we will 1)
delineate the contribution of MMP-3 to phosphate-induced SMC transformation and determine whether it can
promote calcification by degrading ENPP1. 2). Determine whether MMP-3 promotes in vivo arterial calcification
through local actions on medial SMCs or by altering the balance of circulating stimulators and inhibitors, and 3)
Determine whether inhibiting MMP activity with doxycycline can prevent progression of peripheral artery
calcification in a clinical trial. As we progress through these aims we will answer critical questions about the
role of MMPs in arterial calcification and the potential for a dedicated clinical trial to assess the MMP inhibition
strategies aimed at reducing calcification and improving outcomes in our patients with arterial disease.

## Key facts

- **NIH application ID:** 10004162
- **Project number:** 5R01HL138357-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Raul J. Guzman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,538
- **Award type:** 5
- **Project period:** 2019-07-03 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004162

## Citation

> US National Institutes of Health, RePORTER application 10004162, Role of MMPs in arterial calcification (5R01HL138357-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10004162. Licensed CC0.

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