Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A key event in bone resorption is the recruitment of osteoclasts to future resorption sites. We follow here the migration of preosteoclasts from the periosteum to the developing marrow cavity of fetal mouse metatarsals in culture, and investigate the role of proteinases and demineralization in this migration. Our approach consisted in testing inhibitors of proteinases and demineralization on the migration kinetics. Migration was monitored by histomorphometry and the (pre)osteoclasts were identified by their tartrate resistant acid phosphatase (TRAP) activity. At the time of explantation, TRAP+ cells (all mononucleated) are detected only in the periosteum, and the core of the diaphysis (future marrow cavity) consist of calcified cartilage. Upon culture, TRAP+ cells (differentiating progressively into multinucleated osteoclasts) migrate through a seam of osteoid and a very thin and discontinuous layer of mineral, invade the calcified cartilage and transform it into a "marrow' cavity; despite the passage of maturing osteoclasts, the osteoid develops into a bone collar. The migration of TRAP+ cells is completely prevented by matrix metalloproteinase (MMP) inhibitors, but not by a cysteine proteinase inhibitor, an inhibitor of carbonic anhydrase, or a bisphosphonate. The latter three drugs inhibit, however, the resorptive activity of mature osteoclasts at least as efficiently as do the MMP inhibitors, as assessed in cultures of calvariae and radii. Furthermore, in situ hybridizations reveal the expression of 2 MMPs, gelatinase B (MMP-9 or 92 kDa type IV collagenase) in (pre)osteoclasts, and interstitial collagenase (MMP-13) in hypertrophic chondrocytes. It is concluded that only MMPs appear obligatory for the migration of (pre)osteoclasts, and that this role is distinct from the one MMPs may play in the subosteoclastic resorption compartment. We propose that this new role of MMPs is a major component of the mechanism that determines where and when the osteoclasts will attack the bone.
 ...
PMID:Matrix metalloproteinases are obligatory for the migration of preosteoclasts to the developing marrow cavity of primitive long bones. 871 71

Matrix metalloproteinases (MMPs), among which is collagenase (MMP-1), are likely to be involved in various steps of the bone resorption process. As both production of these enzymes and bone resorption appear to be mediated by cytokines, we investigated the effects of two cytokines, IL-1 alpha and EGF, on the release of collagenase, gelatinase A (MMP-2), gelatinase B (MMP-9), TIMP-1 and calcium by rabbit calvariae. It was found that all these parameters increased under the influence of these cytokines. The release of calcium--used as a parameter of bone resorption--was highest in the combined presence of the cytokines. Although the absolute and relative enhancement by a combination of IL-1 alpha and EGF was most pronounced for collagenase (7-fold), both gelatinase A (5-fold) and gelatinase B (1.5-fold) had increased simultaneously. Calvariae produced a high level of MMP inhibitor (TIMP-1), especially under the influence of the cytokines; periosteum released little inhibitor. It is concluded that IL-1 alpha and EGF are likely to play a modulating role in the process of bone resorption.
 ...
PMID:EGF and IL-1 alpha modulate the release of collagenase, gelatinase and TIMP-1 as well as the release of calcium by rabbit calvarial bone explants. 952 23

Like other tissue injuries, bone fracture triggers an inflammatory response, which plays an important role in skeletal repair. Inflammation is believed to have both positive and negative effects on bone repair, but the underlying cellular mechanisms are not well understood. To assess the role of inflammation on skeletal cell differentiation, we used mouse models of fracture repair that stimulate either intramembranous or endochondral ossification. In the first model, fractures are rigidly stabilized leading to direct bone formation, while in the second model, fracture instability causes cartilage and bone formation. We compared the inflammatory response in these two mechanical environments and found changes in the expression patterns of inflammatory genes and in the recruitment of inflammatory cells and osteoclasts. These results suggested that the inflammatory response could influence skeletal cell differentiation after fracture. We then exploited matrix metalloproteinase 9 (MMP9) that is expressed in inflammatory cells and osteoclasts, and which we previously showed is a potential regulator of cell fate decisions during fracture repair. Mmp9(-/-) mice heal stabilized fractures via endochondral ossification, while wild type mice heal via intramembranous ossification. In parallel, we observed increases in macrophages and T cells in the callus of Mmp9(-/-) compared to wild type mice. To assess the link between the profile of inflammatory cells and skeletal cell fate functionally, we transplanted Mmp9(-/-) mice with wild type bone marrow, to reconstitute a wild type hematopoietic lineage in interaction with the Mmp9(-/-) stroma and periosteum. Following transplantation, Mmp9(-/-) mice healed stabilized fractures via intramembranous ossification and exhibited a normal profile of inflammatory cells. Moreover, Mmp9(-/-) periosteal grafts healed via intramembranous ossification in wild type hosts, but healed via endochondral ossification in Mmp9(-/-) hosts. We observed that macrophages accumulated at the periosteal surface in Mmp9(-/-) mice, suggesting that cell differentiation in the periosteum is influenced by factors such as BMP2 that are produced locally by inflammatory cells. Taken together, these results show that MMP9 mediates indirect effects on skeletal cell differentiation by regulating the inflammatory response and the distribution of inflammatory cells, leading to the local regulation of periosteal cell differentiation.
 ...
PMID:MMP9 regulates the cellular response to inflammation after skeletal injury. 2301 Jan 5