Metalloproteinases and their inhibitors—diagnostic and therapeutic opportunities in orthopedics

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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.

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Most cited references 125

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Tetracyclines: nonantibiotic properties and their clinical implications.

Allen Sapadin, Raul Fleischmajer (2006)

Tetracyclines are broad-spectrum antibiotics that act as such at the ribosomal level where they interfere with protein synthesis. They were first widely prescribed by dermatologists in the early 1950s when it was discovered that they were effective as a treatment for acne. More recently, biologic actions affecting inflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolism have been researched. The therapeutic effects of tetracycline and its analogues in various diseases have also been investigated. These include rosacea, bullous dermatoses, neutrophilic diseases, pyoderma gangrenosum, sarcoidosis, aortic aneurysms, cancer metastasis, periodontitis, and autoimmune disorders such as rheumatoid arthritis and scleroderma. We review the nonantibiotic properties of tetracycline and its analogues and their potential for clinical application.

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Tendinopathy--from basic science to treatment.

Lisa Riley (2008)

Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy.

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ADAMs in cancer cell proliferation and progression.

Satsuki Mochizuki, Yasunori Okada (2007)

A disintegrin and metalloproteinases (ADAMs) are a new gene family of proteins with sequence similarity to the reprolysin family of snake venomases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). They are structurally classified into two groups: the membrane-anchored ADAM and ADAM with thrombospondin motifs (ADAMTS). These molecules are involved in various biological events such as cell adhesion, cell fusion, cell migration, membrane protein shedding and proteolysis. Studies on the biochemical characteristics and biological functions of ADAMs are in progress, and accumulated lines of evidence have shown that some ADAMs are expressed in malignant tumors and participate in the pathology of cancers. The activities of ADAMs are regulated by gene expression, intracytoplasmic and pericellular regulation, activation of the zymogens and inhibition of activities by inhibitors. Many ADAM species, including ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19, ADAM28, ADAMTS1, ADAMTS4 and ADAMTS5, are expressed in human malignant tumors. Many of them are involved in the regulation of growth factor activities and integrin functions, leading to promotion of cell growth and invasion, although the precise mechanisms of these are not clear at the present time. In this article, we review recent information about ADAM family members and their implications for cancer cell proliferation and progression.

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Author and article information

Journal

Journal ID (nlm-ta): Acta Orthop

Journal ID (publisher-id): ORT

Title: Acta Orthopaedica

Publisher: Informa Healthcare

ISSN (Print): 1745-3674

ISSN (Electronic): 1745-3682

Publication date (Electronic): 4 December 2009

Publication date (Print): 4 December 2009

Volume: 80

Issue: 6

Pages: 693-703

Affiliations

¹Orthopaedics and Sports Medicine, IKE, Linköping University, Linköping

²Malmö University Hospital, Malmö, Sweden

Author notes

Correspondence: bjorn.pasternak@ 123456gmail.com

Article

Publisher ID: SORT_A_445186_O

DOI: 10.3109/17453670903448257

PMC ID: 2823312

PubMed ID: 19968600

SO-VID: 2359d75d-0a80-485e-8f75-9007ce19bda4

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited.

History

Date received : 25 March 2009

Date accepted : 24 June 2009

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