Matrix metalloproteinases - clearning the way for myeline formation
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AbstractMyelin allows for the rapid conduction of electrical impulses along axons. The breakdown of myelin can have debilitating consequences reflected in diseases such as multiple sclerosis (MS), in which severe demyelination leads to numerous neurological impairments. Strategies to enhance the remyelinating capacity of the myelinating cells, the oligodendrocytes (OLs), are being investigated with the hope of bringing to a halt the demyelinating process. Myelin formation begins with the extension of OL processes to contact axons. Proteolytic activity has been suggested to play a role for OL process extension and this event was suggested to be mediated in part by matrix metalloproteinases (MMPs), and in particular MMP-9. In an attempt to extend these findings, it was hypothesized that MMP-9 activity might also be important in remyelination where the myelinating program is reinitiated after injury. An impaired ability to remyelinate was observed in mice deficient for MMP-9. However, the mechanisms of action did not directly involve process extension but rather a need for MMP-9 to remove proteoglycans that are inhibitory for OL maturation. To elucidate whether other MMP members could also have important functions in OL biology studies on OLs and OL progenitor cells were performed. Purified OL showed high expression of MMP-12 and subsequent experiments revealed that MMP-12 played a role in OL process extension and OL maturation in culture. Finally, it was hypothesized that a deficiency of both MMP-9 and -12 would affect the coordinated developmental myelination and OL biology in vivo. Indeed, these studies showed a transient delay in overall developmental myelination, which was correlated to an excess production of insulin growth factor binding protein-6 (IGFBP-6). This molecule can, by reducing the bioavailability of insulin-like growth factor, act as a negative factor for myelination. Altogether, these data suggest that MMPs are important in controlling the levels of IGFBPs in the environment and thereby regulate the levels of insulin-like growth factor and myelination. Overall, this thesis has uncovered a beneficial mechanism of MMP-9 actions following a demyelinating insult in mice. Furthermore, MMP-12 was implicated in OL biology both in process extension and maturation of these cells. Finally, these proteolytic molecules were found important in the normal timing of initial developmental myelination probably through regulating levels of IGFBPs.
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