MMP inhibition as a potential method to augment the healing of skeletal muscle and tendon extracellular matrix

Abstract

The extracellular matrix (ECM) of skeletal muscle and tendon is composed of different types of collagen molecules that play important roles in the transmission of forces throughout the body, and in the repair and regeneration of injured tissues. Fibroblasts are the primary cells in muscle and tendon that maintain, repair, and modify the ECM in response to mechanical loading, injury, and inactivity. Matrix metalloproteinases (MMPs) are enzymes that digest collagen and other structural molecules, which are synthesized and excreted by fibroblasts. MMPs are required for baseline ECM homeostasis, but disruption of MMP regulation due to injury or disease can alter the normal ECM architecture and prevent proper force transmission. Chronic injuries and diseases of muscles and tendons can be severely debilitating, and current therapeutic modalities to enhance healing are quite limited. This review will discuss the mechanobiology of MMPs, and the potential use of MMP inhibitors to improve the treatment of injured and diseased skeletal muscle and tendon tissue.

Keywords: MMP; TIMP; collagen; extracellular matrix; muscle injury; tendinopathy.

Fig. 1.

Overview of the ultrastructure of skeletal muscle and tendon, demonstrating the interaction between different cell types and their surrounding matrixes.

Fig. 2.

Proposed mechanism of matrix metalloproteinase (MMP)-9 dysregulation and the development of tendinopathy. A: during normal extracellular matrix (ECM) homeostasis, the activities of MMPs and tissue inhibitor of metalloproteinases (TIMPs) are balanced with collagen production. B: in response to increased physiological loading, fibroblasts sense the increased load through interaction with the basement membrane collagens and adjust the activity of MMPs and TIMPs and collagen expression and orientation, which results in an increase in ECM volume and improved ECM organization. C: in cases of chronic injury or unloading, elevated MMP-9 activity leads to degradation of the basement membrane network collagens and the inability of fibroblasts to correctly sense force transmission. Targeted inhibition of MMP-9 could prevent the further progression of chronic disease and may allow for the restoration of a well-organized basement membrane collagen network and allow the fibroblast to properly respond to its environment.