Tumminia and colleagues
1 recently suggested
that human trabecular meshwork cells, used to model juxtacanalicular
cells, respond to mechanical stretch by an alteration in their
cytoskeletal network and signaling cascades. They further postulated
that, in the long-term, the pressure-induced signals could cause“
altered secretion or degradation through changes in the composition
of the extracellular matrix in the extracellular flow pathway that may
be involved in generating outflow resistance.” They state, however,
that these mechanisms remain to be defined.
We would suggest that one excellent candidate for their proposed
stretch homeostatic mechanism already has been established. The
trabecular meshwork–inducible glucocorticoid response protein (TIGR)
is produced by trabecular meshwork cells and then is secreted into the
outflow pathway. TIGR proteins/glycoproteins could have potentially
important interactions with other components of the juxtacanalicular
tissue.
2 3 This region shows a significant concentration
of glycoproteins and glycosaminoglycans and is a likely area for
outflow resistance. The shear stress response of TIGR was suggested
previously on the basis of structural analysis of the
TIGR promoter that revealed four putative sequences that predict its
response to shear stress.
3 In particular, the TIGR protein
is predicted to possess characteristics that could influence outflow
resistance in response to stress or other stimuli. Characteristics of
the TIGR protein include its oligomerization, specific binding to
trabecular meshwork cells, and potential interactions with other
extracellular matrix molecules in the trabecular
meshwork.
3 Tumminia et al.
1 also suggest
that, in glaucoma, these homeostatic mechanisms may be impaired.
Changes in TIGR properties due to structural mutations and/or its
increased expression could be one of the mechanisms involving outflow
obstruction. Several TIGR structure mutations have been confirmed to
associate with glaucoma.
4 5 Abnormal stimulation of
TIGR gene promoter activity by corticosteroids and oxidative
stress were shown to increase TIGR protein expression.
2 Evidence for the overexpression of TIGR in glaucoma comes from the
observation that approximately 50% of eyes with open-angle glaucoma
show notable increases in TIGR staining in the trabecular meshwork
compared with age-matched controls.
6 A sequence variation
in the
TIGR promoter that segregates with affected members
in a large pedigree with primary open-angle glaucoma may also be
relevant.
7
In conclusion, the shear stress response of TIGR suggests that the gene
could have a role as a fluid flow regulator. The TIGR gene/protein in
its cellular and extracellular forms could serve as a homeostatic
stretch response mechanism in the normal eye and play a pathological
role in the disease state. Ongoing research should further unravel the
biology of this interesting gene.