TY - JOUR
T1 - Discrete expression and distribution pattern of TIMP-3 in the human retina and choroid
AU - Vranka, Janice A.
AU - Johnson, Elaine
AU - Zhu, Xianghong
AU - Shepardson, Amy
AU - Alexander, J. Preston
AU - Bradley, John M.B.
AU - Wirtz, Mary K.
AU - Weleber, Richard G.
AU - Klein, Michael L.
AU - Acott, Ted S.
N1 - Funding Information:
This work was funded in part by NIH grants #EY07995, EY03279, EY10572 & EY08247 and by grants from the American Diabetes Association and from Research to Prevent Blindness. Human donor eyes were obtained from the Oregon Lion’s Eye Bank (Portland, OR). Portions of this work were presented in abstract form (61).
PY - 1997
Y1 - 1997
N2 - Purpose. Extracellular matrix homeostasis is dependent in part upon a family of matrix metalloproteinases and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Recently, gene defects in TIMP-3 have been identified in the affected individuals of several families with Sorsby's fundus dystrophy (SFD). Very little information is available regarding TIMP-3 function or even its existence in the retina or choroid. Methods. We used reverse transcription-polymerase chain reaction and Northern analysis to evaluate the expression of TIMP mRNA and Western immunoblots to evaluate TIMP protein produced by select cells of the human retina and choroid. We also used these methods and immunohistochemistry to localize the TIMPs in the retina and choroid. Results. TIMP-3 transcripts are found in cultured human retinal pigment epithelium (RPE), choroidal microcapillary endothelium and pericytes. RPE cells also express and secrete TIMP-3 protein, which is localized to the extracellular matrix and is not found in culture medium; TIMP-1 and -2 are found almost exclusively in the medium. Immunohistochemistry of human retina/choroid sections shows pronounced TIMP-3 immunostaining in Bruch's membrane, particularly near the surface of the RPE and endothelial cells, presumably in their basement membranes, with minimal staining in other portions of the retina. Immunostaining for TIMP-1 is absent and for TIMP-2 is much less prevalent, but detectable in Bruch's membrane. Conclusions. TIMP-1, -2 and -3 exhibit distinctive expression patterns in the retina and choroid. This distribution and expression pattern partially explains why TIMP-3 mutations result in SFD, rather than other retinal pathologies, such as those associated with proliferative diabetic retinopathy.
AB - Purpose. Extracellular matrix homeostasis is dependent in part upon a family of matrix metalloproteinases and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Recently, gene defects in TIMP-3 have been identified in the affected individuals of several families with Sorsby's fundus dystrophy (SFD). Very little information is available regarding TIMP-3 function or even its existence in the retina or choroid. Methods. We used reverse transcription-polymerase chain reaction and Northern analysis to evaluate the expression of TIMP mRNA and Western immunoblots to evaluate TIMP protein produced by select cells of the human retina and choroid. We also used these methods and immunohistochemistry to localize the TIMPs in the retina and choroid. Results. TIMP-3 transcripts are found in cultured human retinal pigment epithelium (RPE), choroidal microcapillary endothelium and pericytes. RPE cells also express and secrete TIMP-3 protein, which is localized to the extracellular matrix and is not found in culture medium; TIMP-1 and -2 are found almost exclusively in the medium. Immunohistochemistry of human retina/choroid sections shows pronounced TIMP-3 immunostaining in Bruch's membrane, particularly near the surface of the RPE and endothelial cells, presumably in their basement membranes, with minimal staining in other portions of the retina. Immunostaining for TIMP-1 is absent and for TIMP-2 is much less prevalent, but detectable in Bruch's membrane. Conclusions. TIMP-1, -2 and -3 exhibit distinctive expression patterns in the retina and choroid. This distribution and expression pattern partially explains why TIMP-3 mutations result in SFD, rather than other retinal pathologies, such as those associated with proliferative diabetic retinopathy.
KW - Bruch's membrane
KW - Choroidal microvasculature
KW - Human
KW - Macular degeneration
KW - Matrix metalloproteinase inhibitor
KW - Retinal pigment epithelium (RPE)
UR - http://www.scopus.com/inward/record.url?scp=0031048533&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031048533&partnerID=8YFLogxK
U2 - 10.1076/ceyr.16.2.102.5086
DO - 10.1076/ceyr.16.2.102.5086
M3 - Article
C2 - 9068940
AN - SCOPUS:0031048533
SN - 0271-3683
VL - 16
SP - 102
EP - 110
JO - Current Eye Research
JF - Current Eye Research
IS - 2
ER -