INDUCTION OF PERLECAN GENE-EXPRESSION PRECEDES AMYLOID FORMATION DURING EXPERIMENTAL MURINE AA AMYLOIDOGENESIS

BACKGROUND: In a murine model of AA amyloidosis, it has been demonstra ted that perlecan, the basement membrane heparan sulfate proteoglycan, is co-deposited with AA amyloid as it forms in various tissues. The o bjectives of this study were to determine whether the accumulation of perlecan during amyloidogenesis is associated with induction of perlec an gene expression and, if so, to define the temporal relationship of this induction to the onset of amyloid formation. EXPERIMENTAL DESIGN: Accelerated splenic AA amyloidosis was stimulated in mice by concomit ant administration of subcutaneous silver nitrate as an inflammatory s timulus and amyloid-enhancing factor. A kinetic analysis of splenic pe rlecan mRNA levels during amyloid formation in the spleen was conducte d using a reverse transcription-polymerase chain reaction assay. Amylo id deposits were detected histochemically with the Congo red stain and by immunohistochemistry using anti-AA antisera. RESULTS: Perlecan mRN A levels increased significantly during amyloidogenesis, increasing 4. 1-fold within 72 hours of the amyloidogenic stimulus and subsequently falling to steady-state levels. A 2.0-fold induction of perlecan mRNA occurred by 24 hours post-stimulation, a time at which amyloid was not detectable by either histochemistry or immunohistochemistry. In contr ast, control animals administered either the inflammatory stimulus or AEF alone showed no significant change in perlecan mRNA levels. CONCLU SIONS: Increased perlecan mRNA levels account, at least in part, for t he accumulation of perlecan in murine splenic AA amyloid deposits. Thi s induction of perlecan gene expression occurs before the onset of amy loid formation, supporting a role for perlecan in the earliest stages of amyloid fibrillogenesis.