Thrombospodin-1 Inhibition of Neovascularization in the Retina and Jaw as a Contributing Factor in Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

Abstract

Purpose : BRONJ is a disorder characterized by ischemia and death to bones of the jaw. BRONJ is most commonly found in patients undergoing bisphosphonate therapy (e.g. Fosamax) for osteoporosis or the hypercalcemia associated with certain cancers. In our previous studies, we created a rat model of BRONJ by two injections of 60ug/Kg zoledronic acid (ZA) via tail vein followed by extraction of a single first molar. This model demonstrated that the vasculature of the jaw, retina and choroid are diminished relative to controls and that bone healing is delayed beyond 4 weeks. The model also showed the changes in jaw vasculature precede the onset of clinically observable osteonecrosis. Since the vasculature of the ocular structures is readily observable with pupil dilation and ocular photography, the association of the changes in vasculature of the jaw with the vasculature of the eye offers a prodrome of BRONJ. The current study was designed to identify angiogenic factors from the jaws and eyes of our established BRONJ model for use in tracking the decreased vascularization associated with the onset and progression of BRONJ.

Methods : Using RT-PCR arrays containing 89 different gene sequences related to angiogenesis, we screened RNA isolated from the jaws and eyes of BRONJ, control, and ZA-treated rats.

Results : Our study shows that the thrombospondin-1 gene is expressed in the tissues of the jaw and eyes in our rat model of BRONJ, but is not expressed in control rats or rats treated with ZA alone without tooth extraction. The significance of this finding is that thrombospondin-1 is known to inhibit neovascularization through the up-regulation of MMP-9, an enzyme necessary for the release of vascular endothelial growth factor (VEGF) from the extracellular matrix to promote angiogenesis.

Conclusions : The expression of thrombospondin-1 exclusively in animals with BRONJ suggests that the role of this molecule in inhibiting the release of VEGF from the extracellular matrix may be a key factor in preventing new blood vessel growth after trauma and promoting the ischemia that ultimately leads to osteonecrosis of the jaw and changes in retinal vasculature.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.