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PubMed2005

Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix.

The extracellular matrix is a three-dimensional network of proteins, glycosaminoglycans and other macromolecules. It has a structural support function as well as a role in cell adhesion, migration, proliferation, differentiation, and survival. The extracellular matrix conveys signals through membrane receptors called integrins and plays an important role in pituitary physiology and tumorigenesis. There is a differential expression of extracellular matrix components and integrins during the pituitary development in the embryo and during tumorigenesis in the adult. Different extracellular matrix components regulate adrenocorticotropin at the level of the proopiomelanocortin gene transcription. The extracellular matrix also controls the proliferation of adrenocorticotropin-secreting tumor cells. On the other hand, laminin regulates the production of prolactin. Laminin has a dynamic pattern of expression during prolactinoma development with lower levels in the early pituitary hyperplasia and a strong reduction in fully grown prolactinomas. Therefore, the expression of extracellular matrix components plays a role in pituitary tumorigenesis. On the other hand, the remodeling of the extracellular matrix affects pituitary cell proliferation. Matrix metalloproteinase activity is very high in all types of human pituitary adenomas. Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis.

Adenoma↗
PubMed2006

Prestorage leukoreduction prevents accumulation of matrix metalloproteinase 9 in stored blood.

OBJECTIVES: Transfusion of aged stored blood is associated with many neutrophil proinflammatory effects. The mechanism of these effects remains to be elucidated. The purpose of this study was to determine whether matrix metalloproteinases accumulate in packed red blood cells during storage and are responsible for some of the neutrophil proinflammatory events, and to determine whether prestorage leukoreduction prevents accumulation of matrix metalloproteinases and attenuates proinflammatory effects of stored packed red blood cells. DESIGN: Laboratory study. PARTICIPANTS: Healthy human volunteers. INTERVENTIONS: Units of blood were drawn from healthy volunteers. Half of each unit was filtered for leukoreduction, removing 99.9% of leukocytes. At biweekly intervals, aliquots were removed from packed red blood cell units, and the plasma fraction was isolated for assays. Plasma was assayed for specific molecules or incubated with isolated neutrophils, with or without a matrix metalloproteinase 9 inhibitor. MAIN OUTCOME MEASURES: Concentrations of matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinase 1; matrix metalloproteinase 9 activity; and neutrophil apoptosis. RESULTS: Concentrations of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 but not matrix metalloproteinase 2 increased over time. This accumulation was abolished by leukoreduction. Matrix metalloproteinase 9 accumulated in an active form. Both leukoreduction and matrix metalloproteinase 9 inhibition reversed stored packed red blood cell-induced, delayed neutrophil apoptosis. CONCLUSIONS: Storage of packed red blood cells for 14 days or more is associated with increases in the concentrations of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1, with the enzyme in excess of its inhibitor. Prestorage leukoreduction prevents this accumulation. Delayed neutrophil apoptosis related to packed red blood cell plasma appears to be due, in part, to matrix metalloproteinase 9. Leukoreduction can help prevent the effects of matrix metalloproteinase 9 on neutrophil apoptosis.

Analysis of Variance↗
PubMed1997

Major internal nuclear matrix proteins are common to different human cell types.

The nuclear matrix may be involved in the structural and functional organization of the cell nucleus. However, we still do not understand the molecular basis of the intranuclear fibrogranular network that is part of the nuclear matrix. We recently described a method to identify internal nuclear matrix proteins [Mattern et al. (1996): J Cell Biochem 62:275-289], which was done by comparing two nuclear matrix preparations: one with and one without the internal structure by using quantitative two-dimensional gel electrophoresis. In the present study, we use the same approach to compare the nuclear matrix proteins of four different human cell types to investigate whether they have a similar internal nuclear matrix protein composition. Major nuclear matrix proteins present in all these cell types likely represent the base of the internal nuclear matrix. We demonstrate that the 25 most abundant internal nuclear matrix proteins are common to all four cell types. Together, these common proteins represent more than 75% of the total internal nuclear matrix protein mass in each cell type. This set of proteins includes B23 and most hnRNP proteins. The quantity of most of these proteins is very similar in the four cell types. The fact that the internal nuclear matrix consists mainly of hnRNP proteins, which may be involved in transcription, transport, and processing of hnRNA, supports the idea that the internal nuclear matrix is the result of these processes.

Carcinoma, Embryonal↗
PubMed1985

Matrix compartments in the growth plate of the proximal tibia of rats.

The cartilaginous matrix in the growth plate of the proximal tibia of rats is subdivided into various compartments according to criteria established by electron microscopic examination. In conventionally fixed specimens, the arrangement of collagen fibrils was analyzed by transmission and scanning electron microscopy. Distribution of proteoglycans and relations between matrix and cells were studied after fixation in media containing cationic dyes. Matrix compartments are best characterized by the density and arrangement of their collagen fibrils. On the other hand, proteoglycans are distributed almost homogenously all over the matrix. Each chondrocyte is surrounded by a thin envelope of proteoglycans, the pericellular matrix. Adjacent to this is a layer dominated by the content and order of its collagen fibrils, the territorial matrix. Its inner part covers the pericellular matrix with a thin net of intersecting fibrils. The outer part unites the cells of each column by a sheath of tightly packed longitudinal fibrils. This distinction is only possible in the longitudinal parts of the territorial matrix, whereas in the transverse septa both layers fuse into a common network. The interterritorial matrix is interposed between the columnar units and thus represents the central part of the longitudinal septa. Mineralization is restricted to the interterritorial matrix and matrix vesicles are coincidentally found in the same compartment. During growth, this structural organization undergoes a permanent and relatively fast remodeling, a process that is discussed in view of possible cell matrix interactions.

Animals↗
PubMed1995

Osteosarcoma hybrids can preferentially target alkaline phosphatase activity to matrix vesicles: evidence for independent membrane biogenesis.

Alkaline phosphatase is the marker enzyme for matrix vesicles, extracellular organelles that play a major role in primary bone formation and calcification. Recently, we developed osteosarcoma x fibrosarcoma hybrids in which alkaline phosphatase expression was greatly reduced, a phenomenon known as extinction. In the present study, we used to cell hybrids, LTA-1 and LTA-5, constructed from a human osteoblast-like osteosarcoma. TE85, and a mouse fibrosarcoma, La-t-, to examine the differential distribution of alkaline phosphatase between matrix vesicles and the plasma membrane, postulated to be the parent membrane from which matrix vesicles are derived. While alkaline phosphatase in plasma membranes was extinguished, enzyme activity in matrix vesicles from LTA-1 hybrid cells was 34.2% of that present in matrix vesicles from the TE85 parent cells and 200 times that found in La-t- matrix vesicles. Matrix vesicles from LTA-5 had alkaline phosphatase levels similar to La-t-. When other membrane enzymes (phospholipase A2, 5'-nucleotidase, and Na+/K+ ATPase) were examined, hybrid matrix vesicle and plasma membrane levels were similar to those of TE85 and significantly higher than in La-t- membrane fractions. Northern analysis detected mRNA for alkaline phosphatase in TE85 cells, but not in the hybrids or La-t- cells. In contrast, reverse transcription-polymerase chain reaction (RT-PCR) revealed alkaline phosphatase mRNA in the hybrid cells, but at very low levels. Taken together, the data indicate that regulation of plasma membrane and matrix vesicle alkaline phosphatase is independent and suggest that matrix vesicle biogenesis is independent and distinct from that of plasma membrane biogenesis. Analysis of 1B- and 1L-type alkaline phosphatase mRNA by RT-PCR showed that alternate promoter usage of the alkaline phosphatase gene was not responsible for the differential localization of this enzyme in matrix vesicle. Thus, it is likely that matrix vesicle and plasma membrane alkaline phosphatase are regulated differently at a post-transcriptional level.

5'-Nucleotidase↗
PubMed1992

Basolateral distribution of fibronectin matrix assembly sites on vascular endothelial monolayers is regulated by substratum fibronectin.

Endothelial cells exhibit binding sites for the amino terminus of fibronectin that participate in subendothelial fibronectin matrix assembly. These binding sites, termed matrix assembly sites, are localized on the basolateral surface of confluent endothelial monolayers (Kowalczyk et al. Blood, 75:2335, 1990). The present study investigates the role of cell-cell and cell-substratum interactions in the localization of matrix assembly sites to the basal surface of endothelial cells. Cells were cultured in Transwell culture inserts and matrix assembly sites were detected by binding assays using an iodinated 70 Kd amino-terminal fibronectin fragment. Integrity of intercellular junctions was monitored by measuring protein flux across Transwell filters. Time course experiments demonstrated that matrix assembly site expression on the basolateral cell surface preceded intercellular junction formation. Transfer of confluent monolayers to calcium-free medium resulted in the loss of junctions and in an increase in 125I-70 kD binding from the apical medium. The increased 125I-70 kD binding resulted from increased access of 125I-70 kD to basolateral matrix assembly sites and not from the relocation of binding sites to the apical membrane. To determine the effect of matrix composition on matrix assembly site expression and localization, cells were seeded onto vitronectin- or fibronectin-coated substrates. Fibronectin increased the expression of matrix assembly sites on the apical surface within 24 hours. By 48 hours, matrix assembly sites were located only on the basolateral surface. Vitronectin had no effect on the expression or localization of matrix assembly sites. These results indicate that the expression and localization of matrix assembly sites on the surface of vascular endothelial cells can be regulated by substratum fibronectin.

Animals↗
PubMed1994

Matrix vesicles produced by osteoblast-like cells in culture become significantly enriched in proteoglycan-degrading metalloproteinases after addition of beta-glycerophosphate and ascorbic acid.

Matrix vesicles, media vesicles, and plasma membranes from three well-characterized, osteoblast-like cells (ROS 17/2.8, MG-63, and MC-3T3-E1) were evaluated for their content of enzymes capable of processing the extracellular matrix. Matrix vesicles were enriched in alkaline phosphatase specific activity over the plasma membrane and contained fully active neutral, but not acid, metalloproteinases capable of digesting proteoglycans, potential inhibitors of matrix calcification. Matrix vesicle enrichment in neutral metalloproteinase varied with the cell line, whereas collagenase, lysozyme, hyaluronidase, and tissue inhibitor of metalloproteinases (TIMP) were not found in any of the membrane fractions examined. MC-3T3-E1 cells were cultured for 32 days in the presence of ascorbic acid (100 micrograms/ml), beta-glycerophosphate (5 mM), or a combination of the two, to assess changes in matrix vesicle enzymes during calcification. Ascorbate or beta-glycerophosphate alone had no effect, but in combination produced significant increases in both active and total neutral metalloproteinase in matrix vesicles and plasma membranes, with the change seen in matrix vesicles being the most dramatic. This correlated with an increase in the formation of von Kossa-positive nodules. The results of the present study indicate that osteoblast-like cells produce matrix vesicles enriched in proteoglycan-degrading metalloproteinases. In addition, the observation that matrix vesicles contain significantly increased metalloproteinases under conditions favorable for mineralization in vitro lends support to the hypothesis that matrix vesicles play an important role in extracellular matrix processing and calcification in bone.

3T3 Cells↗
PubMed2000

Membrane-type 1 matrix metalloproteinase mRNA expression in colorectal cancer.

PURPOSE: Membrane-type matrix metalloproteinases are recently described proteolytic enzymes belonging to the matrix metalloproteinase family. Initial studies have indicated that membrane-type matrix metalloproteinases are involved in tumor invasion and metastasis. Membrane-type 1 matrix metalloproteinase is the first membrane-type matrix metalloproteinase to be described. The aim of this study was to investigate the expression of membrane-type 1 matrix metalloproteinase mRNA in colorectal cancer. METHODS: Samples were collected from surgical specimens of patients with colorectal adenocarcinoma and were immediately frozen in liquid nitrogen and stored at -80 degrees C until processed. Both normal and cancer tissue was taken from each patient. TNM stage, tumor differentiation, mucin production, and vascular invasion were assessed. Northern blotting was used to quantify membrane-type 1 matrix metalloproteinase mRNA levels in the samples using a membrane-type 1 matrix metalloproteinase cDNA clone. X-ray film images were digitized and densitometry was used to quantify bands. All samples were normalized against 18S rRNA levels. Results are expressed as the ratio of cancer to normal tissue levels. Statistical analysis was performed using analysis of variance, with P < 0.05 accepted as the level of significance. RESULTS: A total of 32 samples were prospectively analyzed. The correlation between TNM stage and increased expression of membrane-type 1 matrix metalloproteinase mRNA in cancer tissue over normal tissue is expressed in the mean ratio of cancer to normal tissue expression for Stages I through IV, respectively: 1.4 +/- 0.2 (12 patients); 4.1 +/- 2.6 (8 patients); 3.4 +/- 3 (7 patients); and 4.5 +/- 5 (5 patients). Stage I is significantly different from Stages II and IV (P < 0.05). These preliminary results show an overall increasing trend in membrane-type 1 matrix metalloproteinase expression with increasing tumor stage. However, there was no correlation between membrane-type 1 matrix metalloproteinase expression and mucin production, degree of tumor differentiation, or vascular invasion. CONCLUSION: Preliminary results indicate that membrane-type 1 matrix metalloproteinase levels correlate with increasing tumor stage.

Adenocarcinoma↗
PubMed1991

Retinol-induced modification of the extracellular matrix of endothelial cells: its role in growth control.

The growth of the endothelial cell (EC) is tightly regulated throughout the body. Many factors have been implicated in modulating EC growth including diffusible compounds, cell-to-cell interactions, and the extracellular matrix (ECM). Retinol, or vitamin A alcohol, has recently been shown to inhibit the growth of bovine capillary ECs, in vitro. Retinoids are known to modify ECM in other cell systems, and pure ECM components have been shown to effect EC growth rates. We, therefore, examined the role of the matrix in the retinol-induced inhibition of ECs. Cell-free matrices from control and vitamin A-treated ECs were prepared by removing cells with EGTA treatment after 7 d of culture. Matrix proteins were analyzed by solubilizing the matrices in 5 M guanidine-HCl and performing Western blot analysis using specific antibodies to matrix proteins. In isolating the ECM, we observed that retinol-treated cultures of ECs were resistant to EGTA removal; retinol-treated ECs required twice the exposure time to EGTA to detach from their matrix than did controls cells. Western blot analysis of matrix proteins derived from control and retinol-treated EC cultures demonstrated a 1.6-fold increase in laminin beta chains and a 2.5-fold increase in fibronectin in the ECM of retinol-treated EC compared to control cell matrix. Functional properties of these matrices were assessed by plating control and Day 6 retinol-treated ECs onto the matrices and measuring attachment and growth by determining cell numbers at 24, 72, and 144 h. These studies revealed that control cells attached in greatest numbers to a control matrix whereas retinol-treated ECs preferentially attached to a matrix derived from retinol-treated cells. Furthermore, control ECs which grew rapidly on a control matrix were growth inhibited on a retinol-derived matrix. These data indicate that vitamin A treatment of ECs effects both their phenotype and influences the composition and the functional properties of their underlying ECM. These studies also demonstrate that alterations of the matrix are at least in part responsible for the growth inhibition of EC by retinol.

Animals↗
PubMed2006

Effect of recombinant human tissue inhibitor of matrix metalloproteinase-1 in rabbit mandibular distraction osteogenesis: a histological and immunohistochemical study.

BACKGROUND: Bone matrix metalloproteinases are capable of degrading bone matrix during the remodelling, and their degradation activities can be down regulated by the tissue inhibitors of matrix metalloproteinases. This study evaluated the influence of exogenous tissue inhibitor of matrix metalloproteinase-1 on the expression of matrix metalloproteinases and endogenous tissue inhibitor of matrix metalloproteinases in mandibular distraction osteogenesis. MATERIAL AND METHODS: Fifteen New Zealand white rabbits were assigned to three groups: a negative control; a sham control group implanted with a collagen sheet; and an experimental group implanted with recombinant human tissue inhibitor of matrix metalloproteinase-1 impregnated in a collagen sheet. Rabbits were sacrificed at 6 weeks, 12 weeks and 24 weeks of consolidation. RESULTS: Major expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases was observed at the early stage of consolidation, only positive signals of tissue inhibitors of matrix metalloproteinases were observed at 24 weeks. The addition of recombinant human tissue inhibitor of matrix metalloproteinases-1 did not affect bone maturation and remodelling. CONCLUSIONS: An equilibrium of bone formation and resorption was reached at 24 weeks of consolidation in the rabbit mandible. No obvious influence of recombinant human tissue inhibitor of matrix metalloproteinase-1 on bone remodelling of mandibular distraction osteogenesis was noted.

Animals↗
PubMed2005

Computed tomographic images reflect the biologic behavior of small lung adenocarcinoma: they correlate with cell proliferation, microvascularization, cell adhesion, degradation of extracellular matrix, and K-ras mutation.

BACKGROUND: We previously reported that the computed tomographic M/L ratio (area of the tumor in the mediastinal computed tomographic image/area of the tumor in the lung computed tomographic image) of small peripheral lung adenocarcinoma is correlated with patient prognosis. METHODS: Immunostaining for p53, bcl-2, Ki-67, vascular endothelial growth factor, CD34, matrix metalloproteinase 2, matrix metalloproteinase 9, tissue inhibitor of matrix metalloproteinase 2, and mutation of K-ras was assessed in 131 surgically resected, primary peripheral lung adenocarcinomas of 30 mm or less in maximum diameter to clarify the relationship between computed tomographic findings and biologic activities. RESULTS: The numbers of patients with high labeling indexes of Ki-67 and high expression of vascular endothelial growth factor, CD34, matrix metalloproteinase 2, and matrix metalloproteinase 9 in the solid-type group (computed tomographic M/L ratio > or = 50%) were significantly higher than those in the faint density-type group (computed tomographic M/L ratio < 50%; P = .04 for Ki-67, P = .03 for vascular endothelial growth factor, P = .0009 for CD34, P = .001 for matrix metalloproteinase 2, and P = .00001 for matrix metalloproteinase 9). The number of patients with high levels of CD44v6 or tissue inhibitor of matrix metalloproteinase 2 staining in the faint density-type group was significantly higher than that in the solid-type group (P = .02 for CD44v6 and P = .01 for tissue inhibitor of matrix metalloproteinase 2). Independent variables capable of predicting computed tomographic M/L ratio included CD34, matrix metalloproteinase 2, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 2 (P = .0093, P = .0003, P = .0027, and P = .01, respectively; binary logistic regression analysis). CONCLUSIONS: Our results suggest that the computed tomographic image of small lung adenocarcinoma is correlated with biologic activities and thus provides possible prognostic information.

Adenocarcinoma↗
PubMed1983

Homology of bone-inductive proteins from human, monkey, bovine, and rat extracellular matrix.

Allogeneic implantation of rat extracellular demineralized diaphyseal bone matrix in subcutaneous sites induces a sequence of events resulting in the local differentiation of endochondral bone. However, xenogenic subcutaneous implantation of human, monkey, and bovine extracellular bone matrix into rat showed that bovine matrix had only a weak capacity to induce bone, whereas human and monkey matrix had none at all. This suggested that extracellular matrix-induced bone differentiation is apparently species-specific. We recently reported that the extraction of matrix with 4 M guanidine X HCl resulted in complete removal of the ability to induce endochondral bone differentiation, with the biological activity of the matrix being again restored when the extracted active matrix components (less than 50,000 daltons) were reconstituted with the inactive residue. To define the possible biochemical basis of species specificity, human, monkey, and bovine extracellular bone matrices were extracted with 4 M guanidine X HCl and the extracts were reconstituted with biologically inactive rat residue and bioassayed. The results were similar to those obtained with intact matrices and showed that total extracts of bovine matrix had a weak capacity to induce bone, whereas corresponding extracts of human and monkey matrix did not induce bone. However, partial purification by gel filtration of 4 M guanidine X HCl extracts from each species followed by reconstitution of the different fractions with inactive rat residue resulted in bone induction by all species from fractions containing proteins of less than 50,000 daltons. These observations demonstrate that species specificity of xenogenic extracellular bone matrix is due to immunogenic or inhibitory components (or both) in the guanidine X HCl residue and solubilized extracellular matrix components of greater than 50,000 daltons. These results imply that there is homology in the bone inductive proteins from human, monkey, bovine, and rat extracellular bone matrices.

Animals↗
PubMed1997

Regulated production of mineralization-competent matrix vesicles in hypertrophic chondrocytes.

Matrix vesicles have a critical role in the initiation of mineral deposition in skeletal tissues, but the ways in which they exert this key function remain poorly understood. This issue is made even more intriguing by the fact that matrix vesicles are also present in nonmineralizing tissues. Thus, we tested the novel hypothesis that matrix vesicles produced and released by mineralizing cells are structurally and functionally different from those released by nonmineralizing cells. To test this hypothesis, we made use of cultures of chick embryonic hypertrophic chondrocytes in which mineralization was triggered by treatment with vitamin C and phosphate. Ultrastructural analysis revealed that both control nonmineralizing and vitamin C/phosphatetreated mineralizing chondrocytes produced and released matrix vesicles that exhibited similar round shape, smooth contour, and average size. However, unlike control vesicles, those produced by mineralizing chondrocytes had very strong alkaline phosphatase activity and contained annexin V, a membrane-associated protein known to mediate Ca2+ influx into matrix vesicles. Strikingly, these vesicles also formed numerous apatite-like crystals upon incubation with synthetic cartilage lymph, while control vesicles failed to do so. Northern blot and immunohistochemical analyses showed that the production and release of annexin V-rich matrix vesicles by mineralizing chondrocytes were accompanied by a marked increase in annexin V expression and, interestingly, were followed by increased expression of type I collagen. Studies on embryonic cartilages demonstrated a similar sequence of phenotypic changes during the mineralization process in vivo. Thus, chondrocytes located in the hypertrophic zone of chick embryo tibial growth plate were characterized by strong annexin V expression, and those located at the chondro-osseous mineralizing border exhibited expression of both annexin V and type I collagen. These findings reveal that hypertrophic chondrocytes can qualitatively modulate their production of matrix vesicles and only when induced to initiate mineralization, will release mineralization-competent matrix vesicles rich in annexin V and alkaline phosphatase. The occurrence of type I collagen in concert with cartilage matrix calcification suggests that the protein may facilitate crystal growth after rupture of the matrix vesicle membrane; it may also offer a smooth transition from mineralized type II/type X collagen-rich cartilage matrix to type I collagen-rich bone matrix.

Animals↗
PubMed1993

Renal matrix and adhesion in injury and inflammation.

Over the past year, there have been major advances in the descriptive analysis of the extracellular matrix in the kidney. Several aspects of the interaction of matrix molecules with renal and, in particular with glomerular cells via specific integrin receptors, have also been studied. Most results on cell-matrix interactions have been obtained by in vitro investigations of glomerular mesangial cells in two-dimensional culture. The regulation of matrix formation and degradation has been shown to involve the concerted action of several soluble factors, notably transforming growth factor-beta, as well as the effects of nonsoluble matrix components themselves, such as collagens and proteoglycans. The mediation of such complex interactions between cells, matrix, and cytokines is facilitated by the tightly regulated expression of cell surface receptors, eg, cytokine receptors and integrins of the beta 1 series, which bind specific matrix molecules. New results have yielded more insight into the regulation not only of matrix formation but also of the specific interactions between cells and matrix and of the modulation of cytokine activity by matrix molecules. Using experimental rat models and transgenic mouse models of kidney disease, the first in vivo findings using immunohistochemistry and mRNA analysis have confirmed that major changes occur in the expression of matrix molecules, integrins, and cytokines in the process of glomerular inflammation. With the advent of specific modulators of the bioactivity of ligands and receptors, it is hoped that more information will be forthcoming on the functional relevance of various components of the cell-matrix-cytokine crosstalk in the normal and injured kidney.

Animals↗
PubMed2004

Osteochondral defect repair by demineralized cortical bone matrix.

It has been reported that demineralized bone matrix (cortical or trabecular bone) contains intrinsic cytokines. In the present study, we tested allogeneic demineralized bone matrix for its capacity to resurface osteochondral defects in a rabbit model with the assumption that the intrinsic cytokines in demineralized bone matrix will facilitate the recruitment of progenitor cells from bone marrow into the defect. It was further assumed that these intrinsic bioactive factors would modulate these cells to differentiate into osteochondrogenic lineage and, thus, functionally repair the osteochondral defect. The biocompatibility of demineralized bone matrix was first tested by loading rabbit bone-marrow-derived mesenchymal stem cells into porous demineralized trabecular bone matrix that was then cultured for 3 days. The cell growth in demineralized trabecular bone matrix was examined by scanning electron microscopy. Loaded rabbit bone-marrow-derived mesenchymal stem cells attached to the trabeculae of demineralized trabecular bone matrix; some cells appeared to be round and others were spread and contacted other cells. Allogeneic rabbit demineralized cortical bone matrix or demineralized trabecular bone matrix was implanted into a full-thickness osteochondral defect in the load-bearing area of the medial femoral condyle of young adult rabbits. At 6 and 12 weeks after surgery, gross and histological examination showed that the defects were repaired up to 95% of their depth. The repair tissue using demineralized cortical bone matrix was composed of subchondral bone and a top layer of cartilage that was smooth and integrated with the adjacent cartilage in most of the specimens. Most of the repair tissue in the defect filled with demineralized trabecular bone matrix had a fibrillated surface without integration with the adjacent cartilage. These results indicate that demineralized cortical bone matrix may be potentially useful to repair osteochondral defects by managing the host's intrinsic reparative cells.

Animals↗
PubMed2005

Extracellular matrix changes regulate calcium crystal formation in articular cartilage.

PURPOSE OF REVIEW: The pathologic matrix mineralization seen in calcium pyrophosphate dihydrate and basic calcium phosphate deposition diseases identifies a subset of osteoarthritis patients with an unusual joint distribution and rapid progression of disease. Several factors contribute to pathologic matrix mineralization, including changes in the extracellular matrix of articular cartilage. The factors contributing to extracellular matrix changes that promote crystal formation are important and not well understood. Better characterization of these factors will enhance the understanding of the pathogenesis of pathologic matrix mineralization and may identify potential targets for novel therapeutic interventions. RECENT FINDINGS: Histologic studies of cartilage from patients affected by calcium crystal arthritis show changes in the pericellular matrix of articular chondrocytes. The amounts and types of collagens, proteoglycans, and calcium-binding proteins are altered. The mechanisms by which these changes occur remain poorly understood. Recent work, however, has implicated alterations in the chondrocyte phenotype and post-translational matrix-modulating enzymes such as the transglutaminases. SUMMARY: Changes in extracellular matrix are associated with the pathologic matrix mineralization seen in calcium pyrophosphate dihydrate and basic calcium phosphate crystal deposition diseases. The literature on growth plate cartilage provides observations and mechanisms through which extracellular matrix contributes to normal matrix mineralization, and has served as a model on which to base studies in articular cartilage. More studies are warranted to enhance the understanding of how changes in extracellular matrix contribute to crystal deposition diseases.

Calcium Phosphates↗
PubMed2003

Prolonged spinal loading induces matrix metalloproteinase-2 activation in intervertebral discs.

STUDY DESIGN: An established in vivo mouse model of compression-induced disc degeneration was used to investigate the effects of load on matrix catabolism. OBJECTIVES: To determine whether matrix metalloproteinase-2 expression in discs is modulated by mechanical load and to characterize the regulation of matrix metalloproteinase-2 activity. SUMMARY OF BACKGROUND DATA: We have previously shown that static compression of discs elicits changes in tissue architecture consistent with those seen with degeneration. Evidence in the literature demonstrates the existence of matrix metalloproteinases in both healthy and pathologic discs and suggests that mechanical load may influence matrix metalloproteinase expression and activity. METHODS: Static compression was applied to mouse coccygeal discs in vivo for 1, 4, or 7 days, with adjacent discs serving as sham control. An activity assay was used to measure concentrations of active and total matrix metalloproteinase-2, and changes in matrix metalloproteinase-2 gene expression relative to beta-actin were assessed by reverse transcriptase-polymerase chain reaction. RESULTS: Although no change was seen relative to sham after 1 day of load, the proportion of total matrix metalloproteinase-2 that was active increased after 4 days. This elevation was sustained through 7 days of compression, with no significant differences in total matrix metalloproteinase-2 concentrations among discs throughout the range of time points examined. Semiquantitative reverse transcriptase-polymerase chain reaction demonstrated no significant changes in matrix metalloproteinase-2 gene expression at 1 day or 4 days. CONCLUSIONS: In this model, regulation of matrix metalloproteinase-2 activity occurs primarily through enhanced molecular activation of the proenzyme rather than through elevated gene expression or translation. Our results suggest that matrix metalloproteinase-2 may have a role in load-induced changes in disc architecture.

Animals↗
PubMed2004

Evidence of osteoinduction by Grafton demineralized bone matrix in nonhuman primate spinal fusion.

STUDY DESIGN: A nonhuman primate posterolateral lumbar intertransverse process arthrodesis model was used to evaluate osteoinductive bone graft materials. OBJECTIVES: To test two new formulations of Grafton demineralized bone matrix (Flex and Matrix) for evidence of osteoinduction and their potential efficacy as an extender or enhancer for autogenous bone in a previously validated nonhuman primate posterolateral lumbar fusion model. SUMMARY OF BACKGROUND DATA: Whereas several demineralized bone matrix formulations have been shown to be variably osteoinductive in rodent ectopic bone assays and rabbit spine applications, few have demonstrated efficacy in higher species and in more challenging applications such as posterolateral spine fusion. The authors are not aware of any published studies describing any demineralized bone matrix that has been tested in a nonhuman primate posterolateral spine fusion model. METHODS: After approval by the institutional animal care and use committee, eight skeletally mature rhesus macaques underwent single-level posterolateral arthrodesis. In four animals, autograft (4 g/side) was implanted with a piece of human Grafton Flex demineralized bone matrix. In the other four animals, rhesus Grafton Matrix demineralized bone matrix, a new and more porous formulation of Flex, was implanted with autograft (4 g) on one side of the spine, and Matrix with half the amount of autograft (2 g) was implanted on the opposite side. Radiographs were taken at intervals until the animals were killed at 24 weeks. Spinal fusion was evaluated by manual palpation (status was fused or not fused), and computed tomography was done to visualize the amount of bone formation. RESULTS: Fusion was ascertained by palpation in two of four monkeys receiving Flex with autograft and in three of four monkeys receiving Matrix with autograft. Evidence of osteoinduction was seen in all four monkeys on the Matrix with 4 g autograft side, which had larger fusion masses than in the other treatments. Histologic examination showed that the bone formed was normal. CONCLUSIONS: The rhesus Matrix formulation performed better than the human Flex. Evidence of osteoinduction was seen in all four monkeys that received Matrix, which improved the fusion success of autograft. This alone suggested that it might play a role as a graft enhancer, not merely as a graft extender. Human studies are warranted.

Animals↗