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Editors Selection IGR 12-1

Basic Science: Animal models I

Comment by Ernst Tamm on:

54378 Development of a model of elevated intraocular pressure in rats by gene transfer of bone morphogenetic protein 2, Buie LK; Karim MZ; Smith MH et al., Investigative Ophthalmology and Visual Science, 2013; 54: 5441-5455

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Buie and coworkers report on an animal model of elevated intraocular pressure (IOP) in rats. High IOP was generated by adenovirus-mediated gene transfer of bone-morphogenetic protein-2 (BMP2) to ocular cells. To this end, adenovirus carrying the coding sequences of BMP2 was injected into the anterior chamber. Following injection, the rats had an open chamber angle, an increase in IOP over time and a decline in the number of retinal ganglion cells. As such, the data clearly support the assumption that high IOP in those rats induced primary openangle glaucoma (POAG). Clearly this finding is exciting, novel and important, as the field is in high need for animal models to study POAG. The authors should be congratulated for their findings. In addition, the authors hypothesize that the increase in IOP is due to biological changes in the TM, which they term 'calcification'. In support of this hypothesis, they provide data on changes in gene expression in tissues from the iridocorneal angle. The changes are found in genes that are involved in calcification processes elsewhere in the body. While this is an interesting hypothesis, several other issues and explanations should be taken in consideration and investigated in future research: (1) BMP 2 is a very potent growth factor and it is very likely that it will induce a multitude of other genes in the trabecular meshwork including those of other potent signaling molecules. As of now, it is by no means clear that it is really a 'calcification' process that is responsible for the IOP changes observed; (2) The authors did not show that the increase in IOP is caused by changes in resistance or facility of the TM. A potent growth factor such as BMP2 might induce changes elsewhere in the eye, for example in the ciliary body where it might affect aqueous humor production. Along this line, it would be helpful to see, if the adenovirus only infected TM cells. Methods are available to measure outflow facility in rodents. If it is outflow facility that is affected, the model could be very attractive to identify a long list of molecules that are important for the regulation of outflow facility; (3) The authors showed by light microscopy regions of the trabecular meshwork, in which the extracellular matrix looks denser. The problem is that dense regions of the TM are not uncommon in rodent eyes, especially when the tissue is not fixed by perfusion. It would be highly interesting to see ultrastructural data or immunohistochemical data that would characterize the different matrix proteins or others in the trabecular meshwork. In the end, it seems that any follow-up on the hypothesis of 'calcification' in terms of its relevance for POAG requires at this stage a deletion model. If the expression of 'calcification' genes is relevant for high IOP, adenoviral-mediated BMP2 transfer should not work in mouse models (which appear to be available) that are deficient in those genes.

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