Differential regulation of tissue inhibitor of metalloproteinase mRNA expression in response to intracranial injury

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Abstract
Injury to the CNS induces complex cellular and molecular interactions referred to as reactive gliosis. Alterations in the extracellular microenvironment associated with the gliotic response are believed to be the primary cause of regenerative failure of the mature CNS. For injured neurons to reestablish severed connections their processes must explore the extracellular milieu. Thus far, experiments have focused on extracellular matrix (ECM) proteins whose expression is upregulated after CNS injury and that exert inhibitory effects on neurite outgrowth. An intricate balance between ECM synthesis and degradation must be maintained during the tissue remodeling associated with injury. Matrix metalloproteinases (MMPs) are believed to be the main mediators of ECM degradation. MMP activity is tightly regulated by interaction with tissue inhibitors of metalloproteinases (TIMPs). To determine whether TIMPs are expressed during injury-induced matrix remodeling, TIMP expression was examined during reactive gliosis. A stab injury to the mature rat brain leads to the differential regulation of TIMP mRNA expression. Timp-1 and Timp-2 mRNA are significantly upregulated after injury, while the expression of Timp-3 and Timp-4 is unaltered. The expression of Timp-1 in reactive astrocytes and Timp-2 in microglia and neurons suggests these TIMPs may serve distinct functions in response to injury.