Differential effects of ADAMTSs -1, -4, and -5 in the Trabecular Meshwork
Kate Keller 1,
John M Bradley 1,
and
Ted S. Acott 1*
1 Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States
* To whom correspondence should be addressed. E-mail: acott{at}ohsu.edu.
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Abstract |
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Purpose. Matrix metalloproteinases (MMPs) degrade extracellular matrix (ECM) and
increase outflow facility in anterior segment perfusion culture. One group is the
ADAMTSs (a disintegrin and metalloproteinase with thrombospondin type 1 motifs).
This study examines the effects of ADAMTSs -1, -4, and -5 on outflow facility and
investigates their mRNA levels and protein expression in the trabecular meshwork (TM).
Methods. ADAMTS mRNA was quantitated by qRT-PCR in TM cells exposed to TNF
,
IL-1, TGF
2 or mechanical stretch. ADAMTS-4 mRNA was assessed in normal and
glaucomatous human anterior segments perfused at physiological or elevated pressure. Immunofluorescence was used to localize ADAMTSs in human TM cells and tissue. Anterior segments in perfusion culture were treated with recombinant ADAMTSs to determine effects on outflow facility.
Results. Cytokine treatment increased mRNA of all 3 ADAMTSs. Mechanical stretch
increased ADAMTS-4 mRNA but conversely decreased ADAMTSs -1 and -5 mRNA.
ADAMTS-4 mRNA levels increased in response to pressure elevation in normal eyes
and to higher levels in glaucomatous eyes. ADAMTS-4 protein was highly increased in the juxtacanalicular region of the TM in anterior segments perfused at increased pressure. In human TM cells, ADAMTS-4 co-localized with cortactin in podosome- or invadopodia-like structures, but ADAMTSs -1 and -5 did not. Recombinant ADAMTS-4 increased outflow facility in human and porcine anterior segments, whereas recombinant ADAMTSs-1 or -5 did not.
Conclusions. These results show differential responses and expression of ADAMTSs -1, -4, and -5 in human TM cells. Combined, these results suggest that ADAMTS-4 is a potential modifier of outflow facility.
Key Words:
trabecular meshwork, aqueous flow, extracellular matrix, metalloproteinases
