Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Matrix Metalloproteinases: A Review

Majors topics addressed in this review on zinc physiology are ; 1) chemistry and biochemistry; 2) interface of biochemistry and physiology of zinc; 3) physiology and cell and molecular biology; 4) pathology

The biochemical basis of zinc physiology

Rheumatoid arthritis. Pathophysiology and implications for therapy.

The membrane present at the bone-cement interface was retrieved from twenty patients with a loose, non-septic failed total hip replacement at a site clearly remote from the pseudocapsule that reformed postoperatively. The orientation of the membrane was carefully marked to identify the surface in contact with cement. The membrane was studied histologically, histochemically, by cell culture, by organ culture, and by assessment of its ability to synthesize prostaglandin E2 and collagenase. This membrane, rather than being a nondescript so-called fibrous membrane, has the histological and histochemical characteristics of a synovial-like lining. The synovial-like cells are adjacent to the cement layer. Deep to them macrophages predominate. Inflammatory cells are absent. Cell cultures of this membrane contain stellate cells similar to those found in cell cultures of normal and rheumatoid synovial tissue. This membrane has the capacity to produce large amounts of prostaglandin E2 and collagenase. Clinical Relevance: This transformation of tissue at the bone-cement interface in patients with a non-septic, loose total hip component to a synovial-like tissue with the capacity to generate prostaglandin E2 and collagenase may explain the progressive lysis of bone that is seen in some patients with loose cemented total joint implants. Loosening of the component may be a stimulus to the synthetic activity of this tissue, which leads to further resorption of bone. Understanding and the possibility of pharmacological control of this membrane may contribute to improved duration of total joint implants.

The synovial-like membrane at the bone-cement interface in loose total hip replacements and its proposed role in bone lysis.

It has been known for more than 50 years that retinoids, the family of molecules comprising both the natural and synthetic analogues of retinol, are potent agents for control of both cellular differentiation and cellular proliferation (70). In their original clas sic paper describing the cellular effects of vitamin A deficiency in the rat, Wolbach and Howe clearly noted that there were distinct effects on both differentiation and proliferation of epithelial cells. During vitamin A deficiency, it was found that proper differentia tion of stem cells into mature epithelial cells failed to occur and that abnormal cellular differentiation, characterized in particular by excessive accumulation of keratin, was a frequent event. Furthermore, it was noted that there was excessive cellular proliferation in many of the deficient epithelia. Although the conclusion that an adequate level of retinoid was necessary for control of normal cellular differentiation and proliferation was clearly stated in the original paper by Wolbach and Howe, a satisfactory explanation of the molecular mechanisms underlying these effects on both differentiation and proliferation still eludes us more than 50 years later. It was inevitable that the basic role of retinoids in control of cell differentiation and proliferation would eventually find practical application in the cancer field, and there have been great ad vances in this area, particularly for prevention of cancer. Many studies have shown that retinoids can suppress the process of carcinogenesis in vivo in experimental animals (for reviews, see Refs. 7, 33, 51, 54, 56, and 57), and these results are now the basis of current attempts to use retinoids for cancer prevention in humans. Furthermore, there is now an extensive literature on the ability of retinoids to suppress the development of the malignant phenotype in vitro (for reviews, see Refs. 6, 8, 30, and 31 ), and these studies corroborate the use of retinoids for cancer prevention. Finally, most recently, it has been shown that reti noids can exert effects on certain fully transformed, invasive, neoplastic cells, leading in certain instances to a suppression of proliferation (30) and in other instances to terminal differentiation of these cells, resulting in a more benign, nonneoplastic pheno type (10,11,60,62). Even though there are many types of tumor cells for which this is not the case (33, 52) (indeed, at present there are only a limited number of instances in which such profound effects of retinoids on differentiation and proliferation of invasive tumor cells have been shown), this finding neverthe less has highly significant implications for the problem of cancer treatment. It emphasizes that in many respects cancer is fun damentally a disease of abnormal cell differentiation (36,44), and it raises the possibility that even invasive disease may eventually be controlled by agents which control cell differentiation rather than kill cells. Since carcinogenesis is essentially a disorder of cell differentiation, the overall scientific problem of the role of retinoids in either differentiation or carcinogenesis is essentially

https://cancerres.aacrjournals.org/content/canres/43/7/3034.full.pdf

Role of retinoids in differentiation and carcinogenesis.

Cartilage has a great capacity to resist compressive force. This quality is related to its unique composition of proteinpolysaccharide in a mesh-work of collagen fibers. Although cartilage is not grossly altered in appearance in vitro by incubation with enzymes which can deplete proteinpolysaccharide, it becomes less stiff and more flexible. When slices of canine cartilage were incubated in 0.1M Tris-HCl, pH 7.6, 37°C, without prior freezing or addition of detergents, they spontaneously lost 60% of proteinpolysaccharide by the third day without concomitant loss of collagen. Specimens incubated with trypsin were depleted of 75% proteinpolysaccharide by the first 24 hours and, over a 1-week period, 20% of the collagen, although less than 2% was released during the last 2 days of incubation. Bacterial collagenase resulted in loss of approximately 9% of the total collagen during each day's incubation for 1 week, but the proteinpolysaccharide depletion followed a curve similar to controls. Functional studies, measuring strain under load, indicated that during 24-hour incubations of cartilage treated with trypsin or hyaluronidase these samples had much more evidence of strain than did collagenase-treated specimens. The latter lost actual thickness, however, while the trypsin-treated samples and controls remained the same size, suggesting that collagen has the primary role in determining form of cartilage and may be capable of significant water binding in the absence of proteinpolysaccharide. It is proposed that measurement of compressibility of articular cartilage is a suitable index of its effective proteinpolysaccharide content, and the total volume or thickness can be diminished only by agents capable of removing collagen.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780150505

Effects of proteolytic enzymes on structural and mechanical properties of cartilage.

A series of intracellular events occurring after treatment of rabbit synovial fibroblasts with 0.01 micrograms/ml phorbol myristate acetate (PMA) were measured. Ten minutes after addition of PMA, there was a temporary increase in intracellular cyclic AMP levels, followed by a transient decrease in incorporation of 3H-thymidine into DNA. Approximately 500 ng/mg cell protein of PGE2 were found in culture medium from the 12- to 24-hour incubation period, but significant collagenase was not detectable until 24 to 36 hours. Treatment with aspirin or indomethacin abolished PGE2 production but did not affect collagenase levels. Production of enzyme was associated with a cessation of cell proliferation, measured by protein content/culture and cell number. No enzyme was detectable in untreated cultures. Synovial fibroblasts treated with phorbol myristate acetate may provide a good model for studies on the mechanism of induction of collagenase production.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780221010

Collagenase production by synovial fibroblasts treated with phorbol myristate acetate

Resistance to collagenase: a characteristic of collagen fibrils cross-linked by formaldehyde.

Recent insights into the pathogenesis of the proliferative lesion in rheumatoid arthritis.

Cultures of rheumatoid synovial cells that have been enzymatically dissociated and are adherent to a culture vessel are morphologically heterogeneous. When these cells are cultured on a collagenous substrate for 2 to 6 days at 37 degrees C in serum-free medium, they produce collagenase. A monospecific antibody to human collagenase has localized the enzyme extracellularly around cytoplasmic extensions of dendritic cells and intracellularly within a few macrophage-like and fibroblast-like cells.

Edward D. Harris

Papers

Effects of proteolytic enzymes on structural and mechanical properties of cartilage.

Collagenase production by synovial fibroblasts treated with phorbol myristate acetate

Resistance to collagenase: a characteristic of collagen fibrils cross-linked by formaldehyde.

Recent insights into the pathogenesis of the proliferative lesion in rheumatoid arthritis.

Collagenase immunolocalization in cultures of rheumatoid synovial cells