Updating the role of matrix metalloproteinases in mineralized tissue and related diseases Bone development and healing processes involve a complex cascade of biological events requiring well-orchestrated synergism with bone cells, growth factors, and other trophic signaling molecules and cellular structures. Beyond health processes, MMPs play several key roles in the installation of heart and blood vessel related diseases and cancer, ranging from accelerating metastatic cells to ectopic vascular mineralization by smooth muscle cells in complementary manner. The tissue inhibitors of MMPs (TIMPs) have an important role in controlling proteolysis. Paired with the post-transcriptional efficiency of specific miRNAs, they modulate MMP performance. If druggable, these molecules are suggested to be a platform for development of "smart" medications and further clinical trials. Thus, considering the pleiotropic effect of MMPs on mammals, the purpose of this review is to update the role of those multifaceted proteases in mineralized tissues in health, such as bone, and pathophysiological disorders, such as ectopic vascular calcification and cancer. Bone is a specialized, vascular, and dynamic connective tissue in constant remodeling to maintain physiological ion homeostasis, give support and protection for soft tissue, and be a reservoir of ions important to vertebrates. 1-3 Mechanistically, bone remodeling requires a coordinate and dynamic relationship between deposition/degradation of extracellular matrix (ECM), through growth factors and other signaling molecules, which results in ECM remodeling-an important prerequisite for cell adhesion, migration, proliferation, differentiation. 4 It is well known that osteoclasts resorb the mineralized matrix and further promote the remodeling of the organic fraction of the bone, while, conversely, osteoblasts are responsible for bone formation by depositing specialized ECM components prior to mineralizing it properly 2 . The balance between those specialized cells is crucial for maintaining appropriate bone mass, and the lack of this synchronism contributes to the occurrence of bone diseases, such as osteoporosis and Paget's. To date, ultimate bone cellular differentiation is known to depend on wellorchestrated communication between formation and resorption events. 2,5-7 More specifically, during bone repair after trauma, bone healing depends on interactions between specific signaling inflammatory cytokines and non-resident and eventual cells (such as polymorphonuclear leukocytes and monocyte-macrophage lineage), 8 requiring ECM remodeling by specific matrix metalloproteinases (MMPs). Generally, MMPs are an important family of zinc-dependent endopeptidases and are the major class of enzymes responsible for the degradation or resorption of all ECM components (Figure 1). 9-15 MMP targets include other proteases, protease inhibitors, blood coagulation factors, chemotactic molecules, latent growth factors, binding protein growth factor, cell surface receptors, and cell adhesion molecule...
