Pathologies of matrix metalloproteinase-2 underactivity: a perspective on a neglected condition

Abstract

A member of the matrix metalloproteinase family, matrix metalloproteinase-2 (MMP-2, gelatinase A), has been extensively studied for its role in both normal physiology and pathological processes. Whereas most research efforts in recent years have investigated the pathologies associated with MMP-2 overactivity, the pathological mechanisms elicited by MMP-2 underactivity are less well understood. Here, we distinguish between 2 states and describe their causes: (i) MMP-2 deficiency (complete loss of MMP-2 activity) and (ii) MMP-2 insufficiency (defined as MMP-2 activity below baseline levels). Further, we review the biology of MMP-2, summarizing the current literature on MMP-2 underactivity in both mice and humans, and describe research being conducted by our lab towards improving our understanding of the pathological mechanisms elicited by MMP-2 deficiency/insufficiency. We think that this research could stimulate the discovery of new therapeutic approaches for managing pathologies associated with MMP-2 underactivity. Moreover, similar concepts could apply to other members of the matrix metalloproteinase family.

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

“…Tissue inhibitors of MMPs (TIMPs) are considered suppressors of MMPs in cells. 150 , 151 β-catenin signaling shows interaction with MMPs in HCC that tightly regulates metastasis of these cells. MMP-9 is a target of β-catenin signaling that mediates progression of HCC cells.…”

Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases

“…These observations suggest that bone remodeling may not be solely defined by the balance/imbalance between MMPs and TIMPs. Rather, other molecules expressed and released in the settings of bone physiology and pathology such as RECK (Paiva and Granjeiro, 2014) and some acute phase reactants (alpha 2-macroglobulin, fibrinogen) may regulate/dysregulate MMP activity in inflammatory conditions thus perturbing the normal bone remodeling process (Cook et al, 2018;Sarker et al, 2019). A consequence implied by the latter notion is that MMPs, ADAMs and ADAMTS molecules may be released from bone or non-bone tissues to influence bone remodeling through autocrine and paracrine actions.…”

“…(E) Osteoblasts are recruited to the bone resorption cavity. (F) New osteoid is formed by osteoblasts, and then mineralized (Datta et al, 2008;Fernandez-Patron et al, 2016;Paiva and Granjeiro, 2017;Cook et al, 2018). Other pathologies related to inactive/underactive MMPs are excessive inflammation, cardiovascular disorders, and metabolic dysregulation.…”

“…Other pathologies related to inactive/underactive MMPs are excessive inflammation, cardiovascular disorders, and metabolic dysregulation. MMP underactivity could also result from undesired side effects of common medications with MMP inhibitory actions (e.g., statins) (Cook et al, 2018). MSCs, mesenchymal stem cells; GFs, growth factors; RUNX2, runt-related transcription factor 2; RANKL, receptor activator of NF-kappa B ligand.…”

Evaluation of the Multiple Tissue Factors in the Cartilage of Primary and Secondary Rhinoplasty in Cleft Lip and Palate Patients

“…MMP-2 mediated tissue remodeling plays a role in several physiological mechanisms, such as angiogenesis, neovascularization, and wound healing. Underactivity of MMP-2, either deficiency or insufficiency, has been linked to inflammation, metabolic dysregulation, and skeletal diseases [ 9 , 10 ].…”