Metalloproteinases and their inhibitors-diagnostic and therapeutic opportunities in orthopedics

Abstract

Matrix metalloproteinases (MMPs) and related enzymes (ADAMs, ADAMTS) and their inhibitors control matrix turnover and function. Recent advances in our understanding of musculoskeletal conditions such as tendinopathy, arthritis, Dupuytren's disease, degenerative disc disease, and bone and soft tissue healing suggest that MMPs have prominant roles. Importantly, MMPs are amenable to inhibition by cheap, safe, and widely available drugs such as the tetracycline antibiotics and the bisphosphonates. This indicates that these MMP inhibitors, if proven effective for any novel indication, may be quickly brought into clinical practice.

Figure 1.

Degradation of the extracellular matrix is principally mediated by MMPs, which are counterbalanced by TIMPs. Disturbances of this equilibrium may lead to disease processes of fibrotic nature (left) or degradative nature (right).

Figure 2.

Simplified drawing of MMP regulation. MMP gene transcription is generally induced by stimuli such as inflammatory cytokines, which signal via specific intracellular pathways. MMPs are produced as inactive pro-enzymes that are subsequently cleaved to become active enzymes. MMP-3 appears particularly important in this regard, since it is known to activate several of the MMPs. Plasmin is also an important activator of MMPs. TIMPs inhibit MMPs mainly at the active level. MAPK: mitogen-activated protein kinase.

Figure 3.

Mechanisms of action of tetracyclines. Tetracyclines have several non-antimicrobial effects. The ability of these drugs to inhibit matrix metalloproteinases is well established. Based on this mechanism, tetracyclines have shown clinical effects on rheumatoid arthritis and periodontitis. Doxycycline and minocycline are the two tetracyclines that have been studied most extensively. TNF: tumor necrosis factor; IL: interleukin; NO: nitric oxide; PG: prostaglandin.