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

Neutrophilic leukocytes (PMN) and their precursors from normal human marrow and blood were examined by histochemical staining and by electron microscopy and cytochemistry in order to determine the origin and nature of their cytoplasmic granules. Human neutrophils contain two basic types of granules, azurophils and specifics, which differ in morphology, contents, and time of origin. Azurophils are large and may be spherical or ellipsoid, the latter with a crystalline inclusion. They are produced in the first secretory stage (promyelocyte), contain peroxidase and various lysosomal enzymes, and thus correspond to modified primary lysosomes. Specifics are smaller, may be spherical or elongated, and are formed during a later secretory stage (myelocyte). They lack lysosomal enzymes and contain alkaline phosphatase and basic protein; their contents remain largely undetermined. Specifics outnumber azurophils in the mature PMN because of reduction in numbers of azurophils per cell by cell division in the myelocyte stage. The findings indicate that the situation is basically the same as described previously in the rabbit, insofar as the origin, enzymic activity, and persistence in the mature cell of the two types (azurophil and specific) of granules are concerned. The main difference between PMN of the two species is in the morphology (size, shape, and density) of the granules, especially the azurophils.

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The development of neutrophilic polymorphonuclear leukocytes in human bone marrow origin and content of azurophil and specific granules

Purpose: To integrate information from the various disciplines that contribute to the understanding of the cause and prevention of sudden cardiac death: identification of new approaches from applie...

Sudden Cardiac Death: Epidemiology, Transient Risk, and Intervention Assessment

Bone cells compose a population of cells of heterogeneous origin but restricted function with respect to matrix formation, mineralization, and resorption. The local, mesenchymal origin of the cells which form the skeleton contrasts with their extraskeletal, hemopoietic relatives under which bone resorption takes place. However, the functions of these two diverse populations are remarkably related and interdependent. Bone cell regulation, presently in its infancy, is a complicated cascade involving a plethora of local and systemic factors, including some components of the skeletal matrices and other organ systems. Thus, any understanding of bone cell regulation is a key ingredient in understanding not only the development, maintenance, and repair of the skeleton but also the prevention and treatment of skeletal disorders.

Bone cell biology: the regulation of development structure, and function in the skeleton

The epidemiology of ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) must be explored from multiple aspects, each of which contributes insights into the problem and no one of which exerts exclusive dominance for preventive or therapeutic strategies. These include: (1) population dynamics, using conventional epidemiologic approaches; (2) risk as a function of time from an index event; (3) conditioning risk factors, based on the presence of underlying disease states; (4) transient risk factors that are dynamic and trigger a potentially fatal event at a specific point in time; and (5) “response risk,” which refers to individual susceptibility (possibly determined genetically) to the adverse effects of longitudinal and/or dynamic risk factors. Major inroads into profiling individual or population risk of SCD will require better understanding of each of these epidemiologic-clinical-physiologic interactions. The disciplines range from epidemiology, through clinical medicine, to membrane channel physiology, genetic determinants, and molecular biology.

Frequency of Sudden Cardiac Death and Profiles of Risk

The ultrastructure of erythroblastic islands and reticular cells in mouse bone marrow.

In the transition from proliferation to hypertrophic cell zones in the growth plate, there is an increase in chondrocyte volume and a corresponding decrease in collagen content to accommodate the enlarging cells. It is postulated that collagenase accounts for this collagen loss. To test this hypothesis, tibial growth plates were obtained from normal rats, rachitic rats deficient in vitamin D and phosphate, and rats after 48 and 72 h of healing from rickets. Collagenase was quantitated by a pellet assay based on the release of solubilized collagen from the endogenous insoluble collagen in the tissue homogenates. A fourfold greater collagen release and a concomitant sixfold greater hypertrophic cell volume were measured in rachitic growth plates compared with normal age-matched controls. During healing of rickets, collagenase activity and hypertrophic cell volume returned almost to control levels. Rachitic growth plates were dissected into the juxtaepiphyseal 1/3 and the juxtametaphyseal 2/3. The latter portion contained greater than 95% of the hypertrophic cells and 86% of the collagenase. The collagen-degrading activity was extracted from this region and was shown to be a true collagenase by its production of typical A fragments of tropocollagen produced by collagenase action. The enzyme was activated by aminophenylmercuric acetate and trypsin and was inhibited by EDTA, 1,10-phenanthroline, and a tissue inhibitor of metalloproteinases from human articular cartilage. Inhibitors of aspartic, cysteine, and serine proteases had no effect. Micropuncture fluids aspirated from rachitic cartilage contained latent collagenase activity, indicating an extracellular localization. Negative tests for hemoglobin in the rachitic cartilage samples indicated that there was no contamination by capillaries and that this was not a source of collagenase. It is concluded that extracellular collagenase accounts for the loss of cartilage matrix in the hypertrophic zone, and that this process may be distinct from that of capillary invasion.

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Localization of collagenase in the growth plate of rachitic rats

Nucleation sites for mineralization in rat distal femoral epiphyseal cartilage were studied with the electron microscope Normal, low-phosphate, vitamin D deficient rachitic, and healing rachitic rats were used



The earliest ultrastructural evidence of mineralization in normal animals was the appearance of crystallites inside extracellular matrix vesicles, located in the longitudinal septa of the maturing cell zone in the epiphyseal apparatus The crystallites were absent throughout the entire hypertrophic cell zone of the rachitic specimens



The first evidence of mineralization in rachitic animals treated with both phosphate and vitamin D was the presence of crystallites in the extracellular matrix vesicles These were located in the longitudinal septa of the lower hypertrophic cell zone, near the capillary tufts of the primary spongiosa Crystallites were first detected by 12 hours after treatment; by 24 to 48 hours, the number of matrix vesicles containing crystallites increased substantially



Treatment of rachitic animals with phosphate alone effected the same results as phosphate and vitamin D combined Rachitic animals receiving vitamin D alone did not form mineral in the time periods studied



The results of this investigation support the view that the deposition of mineral in mammalian cartilage requires nucleation sites in the extracellular matrix The findings also are consistent with the hypothesis that membrane-bounded, extracellular matrix vesicles contain the initiating system for calcification of the rat epiphyseal apparatus

Relationship of extracellular matrix vesicles to calcification in normal and healing rachitic epiphyseal cartilage.

Morphometric mapping of regional myocyte diameters after healing of myocardial infarction in cats.

Annulate lamellae have been observed in undifferentiated cells in the marrow of mice treated with urethan They were not found in any recognizable hematopoietic element in either urethan- or saline-injected controls The possibility has been raised that this cytoplasmic organelle is confined to the most primitive marrow cell and may be an identifying feature of 'stem cells'

Irwin Berman

Papers

The ultrastructure of erythroblastic islands and reticular cells in mouse bone marrow.

Localization of collagenase in the growth plate of rachitic rats

Relationship of extracellular matrix vesicles to calcification in normal and healing rachitic epiphyseal cartilage.

Morphometric mapping of regional myocyte diameters after healing of myocardial infarction in cats.

Annulate lamellae in an undifferentiated mouse marrow cell