Although calcification in the cardiovascular system is highly studied, the mechanisms behind it are not well understood. Current proposed mechanisms focus on cellular processes leading to, or controlling the unwanted mineralization in soft tissues. However, extracellular components such as collagen and elastin fundamentally regulate the mechanical properties of heart tissues. Here, we report on a toolkit to control the composition of tissues through the selective digestion of extracellular matrix (ECM) components, which can be used to design disease-specific in vitro models. Using this technique, we show that elastin as well as matrix tissue damage may play major role in cardiovascular calcification. This study highlights a novel approach to understand the role of proteins in soft tissue calcifications and may lead to the development of strategies to treat and prevent these unwanted pathological disorders.