ACCUMULATION OF TISSUE INHIBITOR OF METALLOPROTEINASES-3 IN HUMAN EYES WITH SORSBYS FUNDUS DYSTROPHY OR RETINITIS-PIGMENTOSA

Backgroundlaims-Tissue inhibitor of metalloproteinases-3 (TIMP-3) is n ormally synthesised by the retinal pigment epithelium (RPE) and deposi ted in Bruch's membrane. Mutations in the TIMP3 gene cause Sorsby's fu ndus dystrophy (SFD), which is characterised by thickening of Bruch's membrane, choroidal neovascularisation, and photoreceptor degeneration . To elucidate the role of TIMP-3 in human retinal degenerative diseas es, we immunolocalised TIMP-3 in eyes with SFD caused by the Ser-181-C ys TIMP3 gene mutation or retinitis pigmentosa (RP; not caused by TIMP 3 mutations). Methods-Standard light microscopic immunocytochemistry, including antigen retrieval, was used to localise TIMP-3 in paraffin s ections of human eyes: two with SFD, three with different genetic form s of RP,and two normal. Results-In the SFD eyes, the thickened Bruch's membrane was strongly TIMP-3 positive except where RPE cells had dege nerated. Similarly, in the RP eyes, Bruch's membrane was TIMP-3 positi ve except where RPE cells were lost, consistent with ongoing RPE media ted turnover of TIMP-3 in this region. In areas of total photoreceptor loss, migrated RPE cells formed cuffs around blood vessels in the RP retinas. Thick, TIMP-3 positive extracellular matrix (ECM) deposits as sociated with the migrated RPE cells occluded some vascular lumina, co rrelating with the observed loss of inner retinal neurons in RP. Concl usions-TIMP-3 is a component of the increased ECM sequestered in Bruch 's membrane in SFD. Further information is needed on normal TIMP-3/ECM interactions in Bruch's membrane and the effect of mutant TIMP-3 on t his process. The finding of TIMP-3 accumulations in retinas with RP no t caused by TIMP-3 mutations emphasises the importance of ECM remodell ing in normal and diseased human eyes.